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g_elpot: A Tool for Quantifying Biomolecular Electrostatics from Molecular Dynamics Trajectories
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Biomolecular Systems

g_elpot: A Tool for Quantifying Biomolecular Electrostatics from Molecular Dynamics Trajectories
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  • Andrei Y. Kostritskii*
    Andrei Y. Kostritskii
    Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany
    Department of Physics, RWTH Aachen University, 52062 Aachen, Germany
    Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany
    *E-mail: [email protected]
    More by Andrei Y. Kostritskii
    Orcidhttp://orcid.org/0000-0001-5890-4123
  • Claudia Alleva
    Claudia Alleva
    Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany
    More by Claudia Alleva
  • Saskia Cönen
    Saskia Cönen
    Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany
    Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany
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  • Jan-Philipp Machtens*
    Jan-Philipp Machtens
    Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany
    Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany
    *E-mail: [email protected]. Phone: ++49 2461 614043.
    More by Jan-Philipp Machtens
    Orcidhttp://orcid.org/0000-0003-1673-8571
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Journal of Chemical Theory and Computation

Cite this: J. Chem. Theory Comput. 2021, 17, 5, 3157–3167
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https://doi.org/10.1021/acs.jctc.0c01246
Published April 29, 2021

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Abstract

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Electrostatic forces drive a wide variety of biomolecular processes by defining the energetics of the interaction between biomolecules and charged substances. Molecular dynamics (MD) simulations provide trajectories that contain ensembles of structural configurations sampled by biomolecules and their environment. Although this information can be used for high-resolution characterization of biomolecular electrostatics, it has not yet been possible to calculate electrostatic potentials from MD trajectories in a way allowing for quantitative connection to energetics. Here, we present g_elpot, a GROMACS-based tool that utilizes the smooth particle mesh Ewald method to quantify the electrostatics of biomolecules by calculating potential within water molecules that are explicitly present in biomolecular MD simulations. g_elpot can extract the global distribution of the electrostatic potential from MD trajectories and measure its time course in functionally important regions of a biomolecule. To demonstrate that g_elpot can be used to gain biophysical insights into various biomolecular processes, we applied the tool to MD trajectories of the P2X3 receptor, TMEM16 lipid scramblases, the secondary-active transporter GltPh, and DNA complexed with cationic polymers. Our results indicate that g_elpot is well suited for quantifying electrostatics in biomolecular systems to provide a deeper understanding of its role in biomolecular processes.

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Introduction

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Through shaping the energetics of the interaction between charged substances, electrostatics underlies the biological functions of many biomolecules. Detailed characterization of biomolecular electrostatics is required for a full understanding of diverse biological processes, such as ion transport across cell membranes, protein–ligand interactions, and the formation of biomolecular complexes. Both a biomolecule and its environment contribute to charge distribution and, thereby, to the electrostatic potential of a system. However, experimentally resolved structures rarely provide information on the dynamic biomolecular environment. In the absence of such information, the distribution of the electrostatic potential around a biomolecule can be evaluated by continuum methods based on the Poisson–Boltzmann (PB) equation. (1) Considerable insights into the biophysical properties of proteins and nucleic acids have been gained using continuum methods (1) implemented in a number of software packages, including the widely used DelPhi (2) and APBS. (3,4) However, due to their implicit representation of the biomolecular environment, continuum methods do not take into account a number of molecular-level phenomena (e.g., the orientation of solvent molecules at the interface with biomolecules (5) and the orientation of lipid headgroups around membrane proteins), which can significantly affect the electrostatics of the system. (6) Moreover, PB methods represent the environment in terms of electric permittivity, which is arbitrarily assigned to different parts of the system. (7,8) Lastly, calculations based on the PB equation ignore the natural dynamics of the studied biomolecules. These features limit the amount of quantitative details on biomolecular electrostatics that can be obtained using PB methods.
Nowadays, molecular dynamics (MD) simulations are commonly used to obtain information on the dynamics and functions of biomolecular systems at atomistic resolution. (9,10) During an MD simulation, the biomolecule and its environment sample the conformational space, with each trajectory frame containing information on the instantaneous distribution of electrostatic potential, as defined by the atomic positions. Due to the nanoscale size of the systems studied in MD simulations, periodic boundary conditions are commonly used to avoid undesirable edge effects. (8,11) In a periodic system, the long-range nature of the electrostatics makes the direct sum of contributions from the periodic copies only conditionally convergent. (8) This problem can be tackled by a number of approaches, (8,11) including widely used methods based on the Ewald summation. (12,13) Briefly, the potential is split into short- and long-range parts that converge in real and Fourier spaces, respectively. Whereas the short-range part has singularities at the atom positions, the long-range part can be used to calculate a smooth distribution of the electrostatic potential over the simulation box.
The idea of using the long-range part of the potential (calculated by the smooth particle mesh Ewald (SPME) method (13)) to characterize electrostatics in biomolecular systems based on the MD trajectories was first realized in the pmepot plug-in (14) of the visual molecular dynamics (VMD) package. (15) The plug-in generates a map of the average distribution of the long-range part of the SPME potential and, to the best of our knowledge, has so far been the only tool for extracting electrostatic potentials from MD trajectories. However, the resulting map can be substantially smeared due to the free translation and rotation of a biomolecule during an MD simulation. This smearing cannot be avoided by rotational fitting of the trajectory onto the reference structure prior to the SPME calculation because subsequent application of the periodic boundary conditions results in an artificial electrostatic-potential map. The smearing problem can be solved using short MD trajectories (16) or simulations with positional restraints applied to the biomolecule. (17) However, the absence of a fitting procedure limits the usage of pmepot mainly to the qualitative analysis of electrostatics in long MD simulations of free proteins and nucleic acids. Additionally, although MD trajectories inherently contain time-resolved information on a biomolecular system, pmepot can only derive the average distribution of the potential and not its time course. Furthermore, we will demonstrate that direct quantification of electrostatics from the long-range part of the SPME potential should be interpreted with caution due to its slow convergence over the parameters used for the calculations.
Here, we present the g_elpot tool, which overcomes the aforementioned limitations and enables the efficient quantitative analysis of electrostatic potential in biomolecular systems based on MD trajectories. On-the-fly fitting of trajectory frames enables the generation of high-resolution maps of electrostatic potential around biomolecules. Based on a computational scheme that harnesses the explicit water molecules present in an MD system, g_elpot generates the maps that are easily converted into convergent electrostatic-potential profiles. Using g_elpot, we characterized electrostatics in several biomolecular systems: the P2X3 receptor, human and fungal TMEM16 lipid scramblases, and supramolecular complexes of DNA with polycations. We also exploited the tool’s ability to extract time-resolved electrostatic potentials in arbitrary regions of a biomolecule to quantify the dependence of the electrostatic potential in the substrate-binding pocket on Na+ occupation in the Na+-coupled glutamate transporter homologue GltPh. Taken together, our results demonstrate that g_elpot is a convenient tool for the thorough quantification of electrostatics in diverse biomolecular systems.

Methods

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Quantification of Electrostatics Based on Water-Molecule Potentials

To decide whether it is electrostatically favorable for a charged solvable substance to locate at particular sites on a biomolecule, we consider the potential (Φ) created at a point (r) of a system with respect to the bulk solution
(1)
Defined relative to the bulk, this potential is conceptually equivalent to the PB potential with Dirichlet boundary conditions set to zero. However, in contrast to the PB potential, Φ(r) can be calculated for a particular configuration of a biomolecular system with explicit ions and solvent molecules. Averaging the potential over the MD trajectory, we obtain a distribution of the electrostatic potential while taking into account atomic details of the biomolecular environment.
Hereafter, we only consider the hydrated regions of the system because, in most biologically relevant processes, a charged soluble substance interacts with a biomolecule at a hydrated site. The local electrostatics at the water-populated regions of the system can be quantified by water-molecule potentials that are calculated at a certain point (rwm) within each water molecule, e.g., its center of geometry. The water-molecule potential can then be split into two parts
(2)
where ϕwm(rwm) accounts for the contribution of the water molecule itself to the potential and ϕsur(rwm) is the contribution of the rest of the system, i.e., the surroundings of the water molecule. In turn, we define the system bulk potential as
(3)
where ⟨···⟩bulk denotes averaging over all water molecules in the bulk region of the system. Thus
(4)
The contribution of the water molecule to the potential at rwm depends on the geometry of the water molecule but not on its position or surroundings. Therefore, if water molecules are assumed to have only small geometric fluctuations
(5)
and
(6)
Notably, in the case of absolutely rigid water molecules, the approximations in eqs 5 and 6 become equalities.
In a periodic point-charge system where the unit-cell edges are defined by vectors a1, a2, and a3, the distribution of electrostatic potential can be calculated with the SPME method (13) by splitting the potential into the long-range and short-range parts
(7)
where the long-range part is created by Gaussian-distributed charges ρ(r), approximating the original charge distribution
(8)
where N is the number of atoms, qi and ri are the charge and the position of an atom i, β is the inverse width of a Gaussian, and the outer sum is over n = n1a1 + n2a2 + n3a3, for all integers n1, n2, and n3. The long- and short-range parts of the potential converge in Fourier and real space, respectively. The higher the value of β, the faster the short-range part decays (Supporting Information Figure S1a); therefore, the value of the β parameter can be chosen such that the short-range part of the potential created by an atom is negligible at a predefined distance. In MD simulations, interatomic repulsion at short distances prevents atoms from overlapping and guarantees a nonzero distance between them. Therefore, the short-range part of the potential created at rwm by the atoms surrounding the water molecule can be made negligible by assigning β a value greater than some critical value βc, so
(9)
and Φ can be found as
(10)
Thus, the proper choice of β ensures that only the long-range part of the potential is enough to obtain a rigorous quantification of local electrostatics in the hydrated regions of the simulation system.

Implementation

g_elpot exploits the presence of explicit water molecules in MD simulations to generate detailed information on the electrostatics in a biomolecular system. First, the long-range part of the SPME potential is calculated on a regular grid (Figure 1, step 1), and then each water molecule is assigned a potential, referred to as the water-molecule potential (Figure 1, step 2). This potential is the average of the long-range SPME potentials at the grid nodes within a sphere of 0.15 nm radius around the center of geometry of the water molecule. The averaging smoothens the resulting potentials by suppressing changes in the potential caused by minor changes in the water-molecule geometry. Thus, provided that β ≥ βc, the water-molecule potential can be used to calculate the electrostatic potential created by the water molecule’s surroundings. To avoid smearing of the final electrostatic-potential map (which is built around a biomolecule), the trajectory frame is superimposed on the reference structure of the biomolecule (Figure 1, step 3). Each water-molecule potential is then added to the map nodes that are within 0.15 nm of the water molecule’s center of geometry. After all water-molecule potentials are added to the final electrostatic-potential map, the potential at each node is normalized by the number of contributing water molecules (Figure 1, step 4). This procedure is repeated for each frame of the trajectory, resulting in an average electrostatic-potential map around the biomolecule. g_elpot also generates a map that reports the fraction of trajectory frames in which a particular node has water molecules in its vicinity. Since this map is used to mask the dehydrated regions of a system, it is referred to as a water-occupancy map. As the water-occupancy map has the same dimensions as the electrostatic-potential map, combining both maps is a straightforward way to obtain the electrostatic-potential profile along a coordinate of interest, for instance, along the pore axis of an ion channel. Optionally, the water-molecule-based scheme can be switched off so that the final map is obtained by linear interpolation of the SPME potential instead of the average water-molecule potential. When calculated in this way, the electrostatic-potential map can be used to qualitatively describe the distribution of the electrostatic potential in nonhydrated regions of the system.

Figure 1

Figure 1. Water-based scheme to calculate the electrostatic potential. First, the long-range part of the potential is calculated by solving the Poisson equation on the grid using the SPME method. Second, each water molecule is assigned a potential averaged over a sphere around its center of geometry, resulting in a distribution of water-molecule potentials. Third, the frame is fitted onto the reference structure and the grid of the final electrostatic-potential map is built around the biomolecule. Fourth, the water-molecule potentials are distributed over the nodes of the electrostatic-potential map, followed by normalization of the node potential based on the number of contributing water molecules. The final map is used for the quantitative analysis of electrostatics, e.g., to generate a potential profile.

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g_elpot can also provide time-resolved electrostatic potentials in predefined regions of a system. Each region is defined by a point (the center of geometry of a user-defined group), which is assigned with the average potential of water molecules within a sphere of user-defined radius (Supporting Information Figure S1b). To prevent discontinuity in the resulting time courses, if no water molecule is found within the sphere, then the point is assigned the potential of the nearest water molecule (Supporting Information Figure S1b). The time course of the total number of water molecules within the sphere is also recorded (Supporting Information Figure S1b) so that such dehydrated frames can be excluded from further analysis. To enable comparison with the bulk potential, a point representing the bulk solution must also be specified by the user in absolute coordinates. In practice, the bulk point is chosen based on the initial state of the system but is scaled at every simulation frame following a possible change in the size of the simulation box.
g_elpot is written in C/C++, with the fast Fourier transform as part of the SPME calculation done using FFTW library (18) version 3. OpenMP is used for optional thread parallelization over the trajectory frames. The tool is GROMACS based and, therefore, accepts input files in GROMACS formats. In particular, the atomic charges and reference conformation are read from a tpr file, and the trajectory can be in any GROMACS-supported format (including xtc, tng, trr, and pdb). The atomic groups used for the analysis are defined by the GROMACS-style index file. To apply g_elpot to trajectories generated by other simulation packages, the simulation files need to be converted into GROMACS formats first. In particular, NAMD (19) users can find the conversion instructions at the tool webpage provided below.

Availability and Usage

Source code, installation instructions, and usage recommendations can be found at: https://jugit.fz-juelich.de/computational-neurophysiology/g_elpot.

Simulation Details

P2X3 System

The human ionotropic cation-selective ATP receptor P2X3 was modeled based on its structure in the open state (20) (PDBID: 5SVK) and embedded in a 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayer using the g_membed functionality (21) in GROMACS. The ATP-binding ectodomain (residues 49–315) was cut off, and transmembrane helices were joined by two glycine residues. The system was simulated in GROMACS (22) version 2018 using a time step of 2 fs. A pressure of 1 bar was applied semi-isotropically with a Berendsen barostat (23) using a time constant of 5 ps. A temperature of 310 K was maintained with a velocity-rescaling thermostat. (24) Van der Waals interactions were calculated with the Lennard-Jones potential and a cutoff radius of 1.2 nm, with forces smoothly switched to zero in the range of 1.0–1.2 nm and no dispersion correction. The protein was described by the CHARMM36m (25) force field, lipids by the CHARMM36 force field, (26) and water by the TIP3P model. (27) Na+ and Cl– were added to give a bulk concentration of approximately 150 mM NaCl. To maintain the open state of the P2X3 pore, position restraints were imposed on the backbone atoms of the upper parts of the transmembrane domains (residues 40–45 and 318–323). The production run of 1 μs was preceded by equilibration for about 100 ns: first with restraints on all heavy atoms and lipids in the z-direction, second on all heavy atoms, and third on backbone atoms only. Prior to analysis, the trajectory was sampled every 100 ps. In g_elpot calculations, the SPME grid size was 248 × 248 × 264, and the Cα atoms of residues 21–81 were used as the fitting group.

TMEM16 Systems

Crystal structures of nhTMEM16 (28) (PDBID: 4WIS) and human TMEM16K (29) (PDBID: 5OC9) were used to model the proteins, which were embedded in membranes composed of either pure POPC or a mixture of POPC with 1-palmitoyl-2-oleoyl-phosphatidylserine (POPS). CHARMM36 (26) and CHARMM36m (25) force field parameters were used for lipids and proteins, respectively. The systems were simulated for 1 μs each using GROMACS (22) version 2016 or 2018. Other simulation details are as previously published. (30) Prior to analysis, the trajectories were sampled every 100 ps. In g_elpot calculations, the SPME grid sizes were 360 × 360 × 312 and 390 × 390 × 312 in the nhTMEM16 and TMEM16K systems, respectively. Backbone atoms of residues 182–212, 219–246, 280–319, 324–358, 362–392, 431–464, 499–518, 523–546, 560–585, and 600–625 in nhTMEM16 and backbone atoms of residues 205–235, 239–273, 306–349, 354–388, 392–422, 425–460, 494–512, 517–540, 554–577, and 587–613 in TMEM16K were used as fitting groups.

GltPh Systems

The crystal structure of GltPh in the Na1/Na3-bound state (31) (PDBID: 7AHK) was used to model the protein, which was embedded in a POPC membrane using g_membed, (21) in accordance with the prediction from the Orientations of Proteins in Membranes database. (32) The apo- and Na1-bound states were created by removing the corresponding Na+ ions from the crystal structure. The AMBER99SB-ILDN, (33) Berger, (34) and Joung (35) parameters were used for protein, lipids, and ions, respectively. Simulations were conducted using GROMACS (22) version 5.1. Other simulation details are as previously published (31) (Supporting Information Table S1 shows the simulation times). Prior to the analysis, the trajectories were sampled every 1 ns. In g_elpot calculations, the SPME grid size was 320 × 320 × 272; all backbone atoms were used as the fitting group; and the aspartate-binding site used for time-resolved calculations of the potential was defined as a sphere of 0.7 nm radius around the center of geometry of Cα atoms of residues 276, 277, 278, 309, 394, and 401. Occupancy of the Na1 site was evaluated based on the minimum distance between Na+ ions and the center of mass of backbone oxygen atoms of residues 306, 310, and 401 and of side-chain oxygen atoms of residues 310, 312, and 405. The site was considered occupied if the distance was less than 0.5 nm.

DNA Systems

DNA was in the form of a Dickerson dodecamer (36) and was described by the AMBER parmbsc0 (37) force field. Free DNA in the 150 mM NaCl solution was simulated using GROMACS (22) version 2018. The free-DNA system was first equilibrated using a Berendsen barostat (23) with a time constant of 1 ps: a 5 ns run with restraints on all of the heavy atoms, followed by a 5 ns run with no restraints. The production run was carried out using a Parrinello–Rahman barostat (38) with a time constant of 1 ps. Supporting Information Table S2 shows simulation times for the DNA systems. Simulation details of the DNA–polycation systems can be found in Kondinskaia et al. (39) Prior to analysis, the trajectories were sampled every 100 ps. In g_elpot calculations, the SPME grid size was 200 × 200 × 200, and phosphorus atoms of the DNA molecule were used as the fitting group. To evaluate the equilibrium electrostatics of the complexes, the first 100 ns of the trajectories of DNA with polycations was discarded from the analysis.

Calculating the Electrostatic-Potential Profiles

Electrostatic-potential profiles were calculated by combining a map of the electrostatic potential with a water-occupancy map using the gridData module of the MDAnalysis library. (40) The Python script used to calculate these profiles is available on the tool webpage. The root-mean-square difference (RMSDiff) between two profiles was calculated as
(11)
where Φj(zi) is the potential at the zi position in the j-th profile, and the sum is taken over all of the positions.

Results and Discussion

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Electrostatics within the Cation-Selective Pore of the P2X3 Receptor

P2X receptors are a class of ATP-gated cation channels that are widely expressed in different cell types and essential for a number of physiological processes, including muscle contraction and nociception. (41,42) A functional receptor is formed by three subunits, with each belonging to one of the seven subtypes (41) (P2X1–P2X7) and consisting of two transmembrane helices and a large ATP-binding extracellular domain. (43) Here, we conducted a fully atomistic 1 μs MD simulation of the transmembrane part of the human P2X3 receptor trimer in the open conformation, which was recently resolved by X-ray crystallography. (20) To focus on quantification of electrostatics within the pore region of the receptor (Figure 2a), we substituted the extracellular ATP-binding domain with two glycine residues to connect the transmembrane helices. We then used g_elpot to calculate the electrostatic-potential profile along the P2X3 pore.

Figure 2

Figure 2. Calculation of the electrostatic potential within the pore of the P2X3 cation channel. (a) (Left) Structure of the P2X3 receptor transmembrane domain without the ATP-binding ectodomain and embedded in a lipid membrane. The oxygen and hydrogen atoms of water molecules and the phosphorus atoms around the protein are shown as red, white, and orange spheres, respectively. (Middle) The water-occupancy map, contoured at an occupancy level of 0.1. (Right) Electrostatic-potential map, obtained with β = 20 nm–1 and contoured at −400 mV. The maps were calculated from the first 100 ns block of the 1 μs trajectory. (b) Electrostatic-potential profiles along the P2X3 pore, calculated from the first 100 ns block of the 1 μs trajectory using different values for the β parameter. (c) Average electrostatic-potential profile along the P2X3 pore based on the whole 1 μs trajectory (β = 20 nm–1). Whiskers indicate the standard deviation of the potential, as calculated for 10 separate 100 ns blocks.

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Figure 2a shows examples of the output water-occupancy and electrostatic-potential maps, as calculated from the first 100 ns block of the 1 μs trajectory. Using the water-occupancy map to mask regions with a low water presence (<10 % of frames), we calculated the electrostatic-potential profile along the P2X3 pore by averaging the potential map over the plane perpendicular to the pore axis (Figure 2b,c). Notably, the resulting profile was strongly dependent on the value used for the β parameter in g_elpot calculations (Figure 2b): the potential within the pore was positive if β was <10 nm–1. Higher β values led to more negative potentials, with the profiles converging at a β value of ≥20 nm–1. We also calculated the potential profiles using the raw long-range SPME potential combined with a water-density map produced using GROmaρs (44) (Supporting Information Figure S2a). Although the pore potential was positive at low β values and decreased upon increasing β, the profiles demonstrated poorer convergence over β compared with those calculated using water-based potentials with g_elpot (Supporting Information Figure S2b). A possible explanation for this is that during the trajectory, protein and lipid atoms overlap with the average water-density map and therefore contribute to the resulting potential profiles. However, due to differences in the configuration between water and nonwater molecules, the β parameter affects their internal potentials differently, leading to poorer convergence. As a β value of ≥20 nm–1 provided convergent results, we used it to calculate the average potential profile along the P2X3 pore from the whole 1 μs trajectory (Figure 2c). Consistent with the cation selectivity of the receptor, the electrostatic potential remained negative along the whole pore and reached its lowest values at the intracellular exit of the pore (Figure 2c). To test the convergence of the profiles generated by g_elpot in time, we split the 1 μs trajectory into 10, 50, 100, and 500 ns blocks and calculated an electrostatic-potential profile for each block (Supporting Information Figure S3a). We evaluated the deviation of the obtained profiles from the reference 1 μs profile and found that a trajectory as short as 50 ns is enough to generate a profile, which deviates from the reference on average by <20 mV (Supporting Information Figure S3b). Although in practice convergence of the calculation would always depend on the underlying MD trajectory, we assume that, if all of the relevant states of the system are sufficiently sampled, a trajectory as short as 50 ns would likely suffice to obtain a reasonable estimation of the electrostatic potential.
Our results suggest that use of a low β leads to an artificial electrostatic potential in proximity to nonwater substances and emphasize the importance of using the correct value for the β parameter in electrostatic calculations based on the Gaussian-distributed atomic charges in heterogeneous systems. In particular, a β of 2.5 nm–1, which has been commonly used in studies using pmepot, (45−48) led to the likely incorrect conclusion of a positive electrostatic potential in the cation-selective pore. We demonstrated that using a β value of 20 nm–1 is enough to obtain a convergent potential profile within the pore if the water-based scheme is used. The profile indicated that the negative potential of the pore is focused near its intracellular exit, which is lined by lipid headgroups (Figure 2a). Notably, these lipid headgroups coordinate Na+ ions permeating through the channel. (20,49) Thus, given the high affinity of Ca2+ ions to lipid headgroups, (50,51) our results suggest that the intracellular exit from the P2X3 pore can form a rather deep energetic well in the permeation pathway. Such a well would explain the relatively high Ca2+ permeability of P2X3 receptors, which underlies their role in sensory signal processing. (42,52) In summary, we have demonstrated the advantage of using the electrostatic potential calculated by our water-based method over the raw SPME potential in terms of convergence of the final electrostatic-potential profile, along with the general applicability of g_elpot for quantifying electrostatics in ion channels.

Electrostatics within the Proteolipidic Pores of TMEM16 Lipid Scramblases

TMEM16 lipid scramblases are Ca2+-activated proteins that facilitate the transport of lipids between the leaflets of the membrane. The headgroups of transported lipids slide along the transmembrane hydrophilic cavity exposed by each protomer to the hydrophobic core of the lipid bilayer. (30,53−55) Some lipid scramblases also operate as ion channels, (56) in which the ions permeate through a proteolipidic pore that is partly lined by the lipid headgroups. (30,54) Importantly, the ion selectivity of lipid scramblases is highly variable and depends on the amino acid composition of the pore as well as on the membrane lipid composition. (30) In theory, the distribution of the electrostatic potential within the pore could be used to identify the regions that contribute most to ion selectivity of lipid scramblases. However, the complex and dynamic structure of the proteolipidic pore makes it challenging to obtain comprehensive information on its electrostatic properties using experimental structures only, as they lack the details about lipid arrangement within the cavity. (28,29,57−60) In contrast, MD simulations dynamically sample different configurations of the pore-lining lipids. Here, we used g_elpot to calculate the electrostatic potential along the proteolipidic pores of fungal nhTMEM16 and human TMEM16K in neutral and anionic membranes to gain a better understanding of the connection between electrostatics and ion selectivity in TMEM16 lipid scramblases.
As TMEM16 lipid scramblases form dimers (Figure 3a) of independently acting protomers, (61,62) we first generated electrostatic-potential and water-occupancy maps around the whole protein and then separated the regions corresponding to the different protomers to calculate their electrostatic-potential profiles (Figure 3b,c). In the fully active state, the scramblase cavity is bound to two Ca2+ ions, which were partly hydrated in the simulations. Since the activating Ca2+ ions do not directly interact with the permeating ions, (30) we also excluded from the analysis the regions in direct proximity to the Ca2+ ions (distance of <5 Å). Figure 3b and Figure 3c illustrate the resulting masked water-occupancy maps in the nhTMEM16 and TMEM16K systems, respectively, and Figure 3d shows the final electrostatic-potential profiles along the pores of the TMEM16 lipid scramblases. In full agreement with the higher cation selectivity of nhTMEM16 in anionic compared with neutral membranes, (30) the potential within the nhTMEM16 pore is negative along the whole pore region in the POPC:POPS mixture and is significantly lower than the pore potential in the pure POPC membrane (Figure 3d). The most notable difference between the profiles is seen near the extracellular entrance of the pore (at 10–20 Å along the pore axis), where the potential is about 100 mV more negative in the POPC:POPS than in the POPC membrane. Interestingly, the potential in this region of nhTMEM16 in the POPC:POPS mixture is very similar to that of TMEM16K (Figure 3d). However, the potential in the intracellular part is much more negative in the TMEM16K pore than in the nhTMEM16 pore in either membrane, making the profile negative along the whole pore of TMEM16K and explaining its high cation selectivity. (30)

Figure 3

Figure 3. Electrostatic-potential profiles along the proteolipidic pore of TMEM16 lipid scramblases. (a) Dimeric structure of nhTMEM16 in a lipid membrane. Protomers are colored white and gray; phosphorus atoms are shown in orange. (b,c) Side views of nhTMEM16 in the mixed POPC:POPS membrane (b) and of TMEM16K in the POPC membrane (c), together with the examples of the masked water-occupancy maps used to calculate the electrostatic-potential profiles. The maps were contoured at an occupancy level of 0.1. Phosphorus atoms of POPC and POPS are shown in orange and cyan, respectively. (d) Average electrostatic-potential profiles along the proteolipidic pore of TMEM16K and nhTMEM16 in pure POPC and mixed POPC:POPS membranes. The profiles were averaged over 1 μs trajectories. Whiskers indicate the standard deviation of the potential, as calculated for 10 separate 100 ns blocks.

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Using g_elpot on μs long MD trajectories overcame the limitations of static experimental structures related to the complex and dynamic nature of the proteolipidic pores of nhTMEM16 and TMEM16K. This enabled us to identify the regions responsible for the diverse ion selectivities of these lipid scramblases. We found that anionic lipids mainly affect the ion selectivity of nhTMEM16 by changing the electrostatic potential at the extracellular entrance to the pore. In this region, the negative potential of the nhTMEM16 pore embedded in the anionic membrane is very similar to that of TMEM16K, whose cation selectivity is further strengthened by the negative potential in the intracellular half of its pore. In summary, we have demonstrated that g_elpot is well suited to analyze electrostatics in biomolecular cavities with complex structures and identified the relationship between electrostatics and ion selectivity in TMEM16 lipid scramblases.

Electrostatics in the Substrate-Binding Site of the GltPh Transporter

Excitatory amino acid transporters (EAATs) transport released glutamate from the synaptic cleft back into neurons and glia cells, thereby terminating glutamatergic neurotransmission in the mammalian brain. EAATs are bifunctional homotrimeric proteins that operate as secondary-active transporters and Cl– channels. (63−66) GltPh is a prokaryotic EAAT homologue that has been widely used to study the structural and functional properties of EAATs using MD simulations. (31,66−70) In EAATs, the transport cycle mediates the exchange of one glutamate together with three Na+ and one H+ against one K+. (64) In GltPh, aspartate instead of glutamate is transported together with three Na+ and the inward-to-outward re-translocation is uncoupled from K+ transport. (68,71)
Importantly, the binding of aspartate and Na+ to GltPh is temporally ordered: (31) (i) two Na+ bind consecutively to the Na1 and Na3 sites, (ii) the substrate binds, and (iii) the last Na+ binds to the Na2 site, inducing the conformational changes required to permit inward translocation. As aspartate and Na+ are oppositely charged but do not directly interact with each other when bound to GltPh, electrostatics has been proposed to play an important role in the ion–substrate coupling that defines the stoichiometry of transport. (31) Here, we quantified electrostatics in the aspartate-binding pocket of GltPh in different states to better understand and quantify the role of electrostatics in the energetics of substrate binding in glutamate transporters.
We first simulated GltPh in the apo, Na1, or Na1/Na3-bound states (Figure 4a), ensuring that all three protomers in the protein were in the same state at the start of the simulations (simulations were replicated three times for each state; Supporting Information Table S1). We then used g_elpot to extract time courses of the electrostatic potential in the aspartate-binding site (Figure 4b) from the resulting MD trajectories (Supporting Information Figure S4a). Notably, spontaneous binding of Na+ to the Na1 site (observed in the apo-state simulations; Supporting Information Figure S4b) correlated with an increase in the electrostatic potential of the aspartate-binding pocket (Figure 4b). To compare the electrostatic potential in the different states of GltPh, we split the time courses for each simulated protomer into 50 ns blocks and calculated the average potential in the aspartate-binding site depending on Na+ occupancy (Figure 4c). In simulations starting from the apo state, the protein was considered to be in the Na1-bound state if the average occupancy of the Na1 site in a trajectory block was higher than 0.5. A gradual increase in the potential was seen upon transition from the apo state via the Na1-bound state to the Na1/Na3-bound state. In the apo state, the substrate-binding pocket has negative potential with a median value of −50.7 mV. Although the potential increased upon Na+ binding to the Na1 site, it remained negative in most protomers, with a median value of −13.5 mV. Finally, the potential became positive (median value of 15.3 mV) when both the Na1 and Na3 sites were occupied.

Figure 4

Figure 4. Sodium binding increases the electrostatic potential at the aspartate-binding site of GltPh. (a) Structure of the aspartate-bound GltPh protomer in the outward-facing conformation shown together with different occupancy states of the binding sites. The aspartate molecule is shown in violet, and Na+ ions are shown as blue spheres. The violet cross in the apo panel indicates the position where the potential was measured. Membrane borders are shown schematically. (b) Time courses of electrostatic potential in the aspartate-binding site (violet) and Na+ occupancy of the Na1 site (blue) in one of the protomers upon spontaneous Na+ binding in an MD simulation initiated from the apo state. The time courses are shown as running averages with 50 ns windows. (c) Electrostatic potential in the aspartate-binding site in different states. Each data point is an average potential from a 50 ns block of a single protomer trajectory, whiskers indicate the 5th and 95th percentiles, and a median value is shown for each state.

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Utilizing g_elpot enabled us to quantitatively confirm the previously proposed electrostatic coupling between Na+ and substrate binding in GltPh. (31) The negative potential in the apo- and Na1-bound states facilitates binding of the second Na+ to the Na3 site and energetically disfavors binding of the negatively charged aspartate to the binding pocket. In turn, binding of the second Na+ to the Na3 site reverses the sign of the potential, thus enabling efficient binding of the substrate. This highlights the important role of electrostatics in GltPh transport stoichiometry. In summary, we have demonstrated that the ability of g_elpot to extract time-resolved information on the local electrostatic potential from MD trajectories can provide insight into the energetics of dynamical processes, as demonstrated for the coupling of substrate binding to Na+ binding in the secondary-active transporter GltPh.

Local Effects of Polycations on DNA Electrostatics

The unique physicochemical properties of cationic polymers or polycations make them promising targets for various therapeutic applications, e.g., as antibacterial materials and gene-delivery vectors. (72) These applications are based on the ability of polycations to form complexes with negatively charged biological molecules, including anionic lipids and DNA. Although the binding efficiency of a polycation to anionic membranes or to DNA is mainly defined by its total charge, recent MD simulations have demonstrated that the precise arrangement of the resulting complexes strongly depends on the chemical structure of the polycation. (39,73,74) In particular, the cationic polymers polyvinylamine (PVA) and polyalylamine (PAA) differ structurally only in the length of the side chain of their monomers (Supporting Information Figure S5a) but have distinct binding patterns with a DNA molecule: (39) PAA mainly interacts with the DNA backbone, whereas PVA stably binds to the major groove (Figure 5a). Here, we took full advantage of the fitting functionality of g_elpot to quantify the electrostatics of the DNA grooves and thereby unravel the effects of the polycation-binding pattern on the local electrostatic potential of the resulting supramolecular complex. Since differences in the electrostatic properties of the minor and major grooves of DNA play an important role in DNA condensation, (75) we quantified both the groove-specific and global DNA electrostatics to decipher the effect of polycation-binding patterns on the local electrostatic potential of the resulting polyplex.

Figure 5

Figure 5. Local effects of polycations on DNA electrostatics. (a) Structure of DNA in complex with cationic polymers PVA (left) and PAA (right). The backbone and grooves of DNA are shown in red and white, respectively. Polymers are shown as spheres with nitrogen atoms in blue and carbon atoms in teal (PVA) and yellow (PAA); hydrogen atoms are omitted. (b) Radial distribution of electrostatic potential around the central axis of DNA either in free form or in complex with PVA or PAA, calculated either globally (top), or separately for major (middle) and minor (bottom) grooves. Whiskers indicate the standard deviation of the potential, calculated separately for 100 ns blocks.

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The following scheme was used for groove-specific calculation of the electrostatic-potential profile around DNA. First, each phosphorus atom of the DNA strand was paired with the closest phosphorus atom from the complementary strand based on the interatomic distance along the long axis of the DNA molecule. Since DNA tails are flexible in MD simulations and can occasionally unwind, two phosphorus pairs from each end of the DNA molecule were excluded from the analysis (Supporting Information Figure S5b). The simulation box was then divided along the DNA long axis into 7 Å slabs centered on the center of geometry of each phosphorus pair. Each slab was then split into two subspaces, representing the major and minor grooves (Supporting Information Figure S5c). The subspaces were bounded by two parallel lines drawn through the paired phosphorus atoms on each strand and perpendicular to the line connecting them (Supporting Information Figure S5c).
To compare the effects of the different polycations on DNA electrostatics, we conducted a simulation with DNA in the free form to complement previous simulations of DNA with polycations. (39) When the radial distribution of the electrostatic potential around the central axis of the DNA helix was calculated globally, no significant difference was found between DNA in the free form and in complex with either PAA or PVA at distances larger than 1.2 nm (Figure 5b, top panel). Both polycations had only a minute effect on local minor-groove DNA electrostatics (Figure 5b, bottom panel); in contrast, the difference in their binding patterns resulted in rather distinct effects on the major-groove potential (Figure 5b, middle panel): PVA effectively screened the major groove, whereas PAA shifted the major-groove potential to slightly more negative values compared with the free DNA. This result suggests that polycations can interfere with the charge screening of DNA by Na+ ions. Importantly, the potential distributions differed up to 2.5 nm (i.e., more than twice the DNA radius) from the DNA central axis, suggesting that the polycations would influence the interactions between different DNA segments during condensation.
Thus, by using g_elpot, we found that the groove-specific electrostatics of DNA–polycation complexes are sensitive to small differences in the monomeric structures that determine the binding patterns of polycations to the DNA double helix. The fact that both PVA and PAA had only a minor impact on the global electrostatics of the DNA suggests that the charge density of the polycations may be insufficient to efficiently screen the negative charge of DNA. This is consistent with previous reports that linear polycations have a lower DNA-condensing efficiency than their branched forms. (72) Our calculations also demonstrated that in DNA in the free form, the minor groove creates a significantly greater negative potential compared with the major groove (Figure 5b). This suggests that polycations that effectively screen the minor groove (i.e., similar to histones (75,76)) may reduce the energetic penalty related to DNA condensation more efficiently than polycations that screen the major groove. In summary, we have demonstrated that the fitting functionality of g_elpot enables the quantification of local electrostatics around water-soluble molecules and provided high-resolution insights into the biophysical properties of DNA–polycation complexes.

Conclusions and Perspectives

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Electrostatics plays a substantial role in many biomolecular processes. Since atomic positions define the distribution of the electrostatic potential within a system, atomistic MD simulations are a rich source of detailed structural information that can be harnessed for the high-resolution characterization of electrostatics. In this work, we developed a computational scheme based on the presence of explicit water molecules in biomolecular MD systems for the reliable quantification of the electrostatics of biomolecules based on their MD trajectories. We implemented the scheme in a GROMACS-based (22) tool, called g_elpot, that can be used to generate high-resolution maps and time courses of the electrostatic potential from MD trajectories of biomolecular systems. We have demonstrated that this approach is well suited to gain insights into electrostatics in diverse biomolecular systems, including receptors, ion channels, transporters, and supramolecular complexes of DNA with polycations. We found that the intracellular exit of the P2X3 pore has the lowest electrostatic potential and may form an energetic well for permeating cations. We also identified the regions that define ion selectivity in the proteolipidic pores of ion-conducting TMEM16 lipid scramblases. Furthermore, we demonstrated that electrostatics influences ion–substrate coupling in the secondary-active transporter GltPh by using g_elpot to extract time courses of the electrostatic potential in the substrate-binding pocket. Finally, we quantified the specific effect of polycation-binding patterns on the electrostatics around the DNA major and minor grooves.
In addition to the examples reported here, g_elpot can be generally applied to study the electrostatics of any hydrated macromolecule, including globular proteins and carbon nanotubes. Moreover, owing to its ability to obtain time-resolved electrostatic potentials, the tool can be used in combination with functional mode analysis (77,78) to identify the structural determinants of electrostatic potential in the function-related regions of proteins. Finally, as it is becoming increasingly common to complement experimental structural studies with MD simulations, (20,29,79) g_elpot is an ideal tool for the initial biophysical characterization of newly resolved biomolecular structures. In conclusion, we anticipate that the insights gained with g_elpot will further advance our understanding of the mechanisms linking biomolecular structure and dynamics to physiological function.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jctc.0c01246.

  • Dependence of the short-range part of the potential on β; convergence of P2X3 profiles calculated from the raw SPME potential; time convergence of the g_elpot calculations; raw data on the electrostatic potential and Na1 occupancy in the GltPh simulations; chemical structure of PVA and PAA; groove-specific division of space in DNA systems; and simulation times for DNA and GltPh systems (PDF)

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Author Information

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  • Corresponding Authors
    • Andrei Y. Kostritskii - Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany;  Department of Physics, RWTH Aachen University, 52062 Aachen, Germany;  Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany;  Orcidhttp://orcid.org/0000-0001-5890-4123;  Email: [email protected]
    • Jan-Philipp Machtens - Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany;  Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany;  Orcidhttp://orcid.org/0000-0003-1673-8571;  Email: [email protected]
  • Authors
    • Claudia Alleva - Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany
    • Saskia Cönen - Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, 52425 Jülich, Germany;  Institute of Clinical Pharmacology, RWTH Aachen University, 52062 Aachen, Germany
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors thank Dr. Andrey Gurtovenko for providing trajectories of DNA with polycations and Dr. Christoph Fahlke, Dr. Ralf Hausmann, and Piersilvio Longo for critically reading the manuscript. A.Y.K. thanks Diana Kondinskaia for fruitful discussions. This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) to J.-P.M. (MA 7525/1-2, as part of the Research Unit FOR 2518, DynIon, project P4; and MA 7525/2-1, as part of the Research Unit FOR 6046, project P2) and to Dr. Ralf Hausmann (HA 6095/1-2), the Jülich-Aachen Research Alliance Center for Simulation and Data Science (JARA-CSD) School for Simulation and Data Science (SSD), and by a grant from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (IZKF TN1-3/IA532003). The authors gratefully acknowledge the computing time granted through JARA on the supercomputer JURECA at Forschungszentrum Jülich and the supercomputer CLAIX at RWTH Aachen University.

References

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    Lin, Y.-L.; Aleksandrov, A.; Simonson, T.; Roux, B. An Overview of Electrostatic Free Energy Computations for Solutions and Proteins. J. Chem. Theory Comput. 2014, 10, 2690– 2709,  DOI: 10.1021/ct500195p
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    An Overview of Electrostatic Free Energy Computations for Solutions and Proteins
    Lin, Yen-Lin; Aleksandrov, Alexey; Simonson, Thomas; Roux, Benoit
    Journal of Chemical Theory and Computation (2014), 10 (7), 2690-2709CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    A review. Free energy simulations for electrostatic and charging processes in complex mol. systems encounter specific difficulties owing to the long-range, 1/r Coulomb interaction. To calc. the solvation free energy of a simple ion, it is essential to take into account the polarization of nearby solvent but also the electrostatic potential drop across the liq.-gas boundary, however distant. The latter does not exist in a simulation model based on periodic boundary conditions because there is no phys. boundary to the system. An important consequence is that the ref. value of the electrostatic potential is not an ion in a vacuum. Also, in an infinite system, the electrostatic potential felt by a perturbing charge is conditionally convergent and dependent on the choice of computational conventions. Furthermore, with Ewald lattice summation and tinfoil conducting boundary conditions, the charges experience a spurious shift in the potential that depends on the details of the simulation system such as the vol. fraction occupied by the solvent. All these issues can be handled with established computational protocols, as reviewed here and illustrated for several small ions and three solvated proteins.
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  12. 12
    Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, 10089– 10092,  DOI: 10.1063/1.464397
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    Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems
    Darden, Tom; York, Darrin; Pedersen, Lee
    Journal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.
    An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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  13. 13
    Essmann, U.; Perera, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577– 8593,  DOI: 10.1063/1.470117
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    A smooth particle mesh Ewald method
    Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.; Darden, Tom; Lee, Hsing; Pedersen, Lee G.
    Journal of Chemical Physics (1995), 103 (19), 8577-93CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    The previously developed particle mesh Ewald method is reformulated in terms of efficient B-spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p ≥ 1. Furthermore, efficient calcn. of the virial tensor follows. Use of B-splines in the place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. The authors demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomol. systems with many thousands of atoms and this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 Å or less.
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  14. 14
    Aksimentiev, A.; Schulten, K. Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map. Biophys. J. 2005, 88, 3745– 3761,  DOI: 10.1529/biophysj.104.058727
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    Imaging α-hemolysin with molecular dynamics: Ionic conductance, osmotic permeability, and the electrostatic potential map
    Aksimentiev, Aleksij; Schulten, Klaus
    Biophysical Journal (2005), 88 (6), 3745-3761CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
    α-Hemolysin of Staphylococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, α-hemolysin is the principal component in several biotechnol. applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technol. for DNA sequencing. Through large-scale mol. dynamics simulations, we studied the permeability of the α-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of ∼300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water soln. of KCl. Monitoring the fluctuations of the pore structure revealed an asym., on av., cross section of the α-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of α-hemolysin and a set of electrostatic potential maps. The selectivity of α-hemolysin to Cl- was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quant. agreement with available exptl. data. Analyzing trajectories of all water mol., we computed the α-hemolysin's osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk soln.; the protonation of these residues was obsd. to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the α-hemolysin channel.
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  15. 15
    Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graphics 1996, 14, 33– 38,  DOI: 10.1016/0263-7855(96)00018-5
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    VDM: visual molecular dynamics
    Humphrey, William; Dalke, Andrew; Schulten, Klaus
    Journal of Molecular Graphics (1996), 14 (1), 33-8, plates, 27-28CODEN: JMGRDV; ISSN:0263-7855. (Elsevier)
    VMD is a mol. graphics program designed for the display and anal. of mol. assemblies, in particular, biopolymers such as proteins and nucleic acids. VMD can simultaneously display any no. of structures using a wide variety of rendering styles and coloring methods. Mols. are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resoln. raster images of displayed mols. may be produced by generating input scripts for use by a no. of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate mol. dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biol., which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs, VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
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  16. 16
    Enkavi, G.; Tajkhorshid, E. Simulation of spontaneous substrate binding revealing the binding pathway and mechanism and initial conformational response of GlpT. Biochemistry 2010, 49, 1105– 1114,  DOI: 10.1021/bi901412a
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    Simulation of Spontaneous Substrate Binding Revealing the Binding Pathway and Mechanism and Initial Conformational Response of GlpT
    Enkavi, Giray; Tajkhorshid, Emad
    Biochemistry (2010), 49 (6), 1105-1114CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    Glycerol 3-phosphate transporter (GlpT) mediates the import of glycerol 3-phosphate (G3P) using the gradient of inorg. phosphate (Pi). To study the process and mechanism of substrate binding and to investigate the protein's initial response, we performed equil. simulations of wild-type GlpT and several of its mutant forms in membranes in the presence of all physiol. relevant substrates (Pi-, Pi2-, G3P-, and G3P2-). The simulations capture spontaneous substrate binding of GlpT, driven by the pos. electrostatic potential of the lumen. K80 is found to act as a "hook" making the first encounter with the substrate and guiding it toward the binding site, where it binds tightly to R45, a key binding site residue that acts as a "fork" holding the substrate. R269 establishes no direct contact with the substrate during the simulations, a surprising behavior given its structural pseudosymmetry to R45. In all substrate-bound systems, partial closing of the cytoplasmic half of GlpT was obsd. The substrate appears to stabilize the partially occluded state, as in the two apo simulations either no closing was obsd. or the protein reverted to its open form toward the end of the simulation, whereas in all substrate-bound systems, a stable partially closed state was produced. Along with the modulation of the periplasmic salt bridge network, these substrate-induced events destabilize the periplasmic half while inducing a closure in the cytoplasmic half, thus capturing the early stages of the proposed rocker-switch mechanism in GlpT.
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    Arcario, M. J.; Tajkhorshid, E. Membrane-induced structural rearrangement and identification of a novel membrane anchor in talin F2F3. Biophys. J. 2014, 107, 2059– 2069,  DOI: 10.1016/j.bpj.2014.09.022
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    Membrane-Induced Structural Rearrangement and Identification of a Novel Membrane Anchor in Talin F2F3
    Arcario, Mark J.; Tajkhorshid, Emad
    Biophysical Journal (2014), 107 (9), 2059-2069CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    Exptl. challenges assocd. with characterization of the membrane-bound form of talin have prevented us from understanding the mol. mechanism of its membrane-dependent integrin activation. Here, utilizing what we believe to be a novel membrane mimetic model, we present a reproducible model of membrane-bound talin obsd. across multiple independent simulations. We characterize both local and global membrane-induced structural transitions that successfully reconcile discrepancies between biochem. and structural studies and provide insight into how talin might modulate integrin function. Membrane binding of talin, captured in unbiased simulations, proceeds through three distinct steps: initial electrostatic recruitment of the F2 subdomain to anionic lipids via several basic residues; insertion of an initially buried, conserved hydrophobic anchor into the membrane; and assocn. of the F3 subdomain with the membrane surface through a large, interdomain conformational change. These latter two steps, to our knowledge, have not been obsd. or described previously. Electrostatic anal. shows talin F2F3 to be highly polarized, with a highly pos. underside, which we attribute to the initial electrostatic recruitment, and a neg. top face, which can help orient the protein optimally with respect to the membrane, thereby reducing the no. of unproductive membrane collision events.
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    Frigo, M.; Johnson, S. G. The Design and Implementation of FFTW3. Proc. IEEE 2005, 93, 216– 231,  DOI: 10.1109/JPROC.2004.840301
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    Phillips, J. C.; Hardy, D. J.; Maia, J. D. C.; Stone, J. E.; Ribeiro, J. V.; Bernardi, R. C.; Buch, R.; Fiorin, G.; Hénin, J.; Jiang, W.; McGreevy, R.; Melo, M. C. R.; Radak, B. K.; Skeel, R. D.; Singharoy, A.; Wang, Y.; Roux, B.; Aksimentiev, A.; Luthey-Schulten, Z.; Kalé, L. V.; Schulten, K.; Chipot, C.; Tajkhorshid, E. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J. Chem. Phys. 2020, 153, 044130  DOI: 10.1063/5.0014475
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    Scalable molecular dynamics on CPU and GPU architectures with NAMD
    Phillips, James C.; Hardy, David J.; Maia, Julio D. C.; Stone, John E.; Ribeiro, Joao V.; Bernardi, Rafael C.; Buch, Ronak; Fiorin, Giacomo; Henin, Jerome; Jiang, Wei; McGreevy, Ryan; Melo, Marcelo C. R.; Radak, Brian K.; Skeel, Robert D.; Singharoy, Abhishek; Wang, Yi; Roux, Benoit; Aksimentiev, Aleksei; Luthey-Schulten, Zaida; Kale, Laxmikant V.; Schulten, Klaus; Chipot, Christophe; Tajkhorshid, Emad
    Journal of Chemical Physics (2020), 153 (4), 044130CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    A review. NAMD is a mol. dynamics program designed for high-performance simulations of very large biol. objects on CPU- and GPU-based architectures. NAMD offers scalable performance on petascale parallel supercomputers consisting of hundreds of thousands of cores, as well as on inexpensive commodity clusters commonly found in academic environments. It is written in C++ and leans on Charm++ parallel objects for optimal performance on low-latency architectures. NAMD is a versatile, multipurpose code that gathers state-of-the-art algorithms to carry out simulations in apt thermodn. ensembles, using the widely popular CHARMM, AMBER, OPLS, and GROMOS biomol. force fields. Here, the authors review the main features of NAMD that allow both equil. and enhanced-sampling mol. dynamics simulations with numerical efficiency. The authors describe the underlying concepts used by NAMD and their implementation, most notably for handling long-range electrostatics; controlling the temp., pressure, and pH; applying external potentials on tailored grids; leveraging massively parallel resources in multiple-copy simulations; and hybrid quantum-mech./mol.-mech. descriptions. The authors detail the variety of options offered by NAMD for enhanced-sampling simulations aimed at detg. free-energy differences of either alchem. or geometrical transformations and outline their applicability to specific problems. Last, the roadmap for the development of NAMD and the authors' current efforts toward achieving optimal performance on GPU-based architectures, for pushing back the limitations that have prevented biol. realistic billion-atom objects to be fruitfully simulated, and for making large-scale simulations less expensive and easier to set up, run, and analyze are discussed. NAMD is distributed free of charge with its source code at www.ks.uiuc.edu. (c) 2020 American Institute of Physics.
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    Mansoor, S. E.; Lü, W.; Oosterheert, W.; Shekhar, M.; Tajkhorshid, E.; Gouaux, E. X-ray structures define human P2X(3) receptor gating cycle and antagonist action. Nature 2016, 538, 66– 71,  DOI: 10.1038/nature19367
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    X-ray structures define human P2X3 receptor gating cycle and antagonist action
    Mansoor, Steven E.; Lu, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric
    Nature (London, United Kingdom) (2016), 538 (7623), 66-71CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiol. and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacol. agents.
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    Wolf, M. G.; Hoefling, M.; Aponte-Santamaría, C.; Grubmüller, H.; Groenhof, G. g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation. J. Comput. Chem. 2010, 31, 2169– 2174,  DOI: 10.1002/jcc.21507
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    g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation
    Wolf, Maarten G.; Hoefling, Martin; Aponte-Santamaria, Camilo; Grubmueller, Helmut; Groenhof, Gerrit
    Journal of Computational Chemistry (2010), 31 (11), 2169-2174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    To efficiently insert a protein into an equilibrated and fully hydrated membrane with minimal membrane perturbation the authors present a computational tool, called g_membed, which is part of the Gromacs suite of programs. The input consists of an equilibrated membrane system, either flat or curved, and a protein structure in the right position and orientation with respect to the lipid bilayer. G_membed first decreases the width of the protein in the xy-plane and removes all mols. (generally lipids and waters) that overlap with the narrowed protein. Then the protein is grown back to its full size in a short mol. dynamics simulation (typically 1000 steps), thereby pushing the lipids away to optimally accommodate the protein in the membrane. After embedding the protein in the membrane, both the lipid properties and the hydration layer are still close to equil. Thus, only a short equilibration run (less then 1 ns in the cases tested) is required to re-equilibrate the membrane. Its simplicity makes g_membed very practical for use in scripting and high-throughput mol. dynamics simulations. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.
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    Abraham, M. J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J. C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015, 1–2, 19– 25,  DOI: 10.1016/j.softx.2015.06.001
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    Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 1984, 81, 3684– 3690,  DOI: 10.1063/1.448118
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    Molecular dynamics with coupling to an external bath
    Berendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.
    Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.
    In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
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    Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007, 126, 014101  DOI: 10.1063/1.2408420
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    Canonical sampling through velocity rescaling
    Bussi, Giovanni; Donadio, Davide; Parrinello, Michele
    Journal of Chemical Physics (2007), 126 (1), 014101/1-014101/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    The authors present a new mol. dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains const. during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. The authors illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liq. phases. Its performance is excellent and largely independent of the thermostat parameter also with regard to the dynamic properties.
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    Huang, J.; Rauscher, S.; Nawrocki, G.; Ran, T.; Feig, M.; de Groot, B. L.; Grubmüller, H.; MacKerell, A. D. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 2017, 14, 71– 73,  DOI: 10.1038/nmeth.4067
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    CHARMM36m: an improved force field for folded and intrinsically disordered proteins
    Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz; Ran, Ting; Feig, Michael; de Groot, Bert L.; Grubmuller, Helmut; MacKerell, Alexander D. Jr
    Nature Methods (2017), 14 (1), 71-73CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    The all-atom additive CHARMM36 protein force field is widely used in mol. modeling and simulations. We present its refinement, CHARMM36m (http://mackerell.umaryland.edu/charmm_ff.shtml), with improved accuracy in generating polypeptide backbone conformational ensembles for intrinsically disordered peptides and proteins.
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  26. 26
    Klauda, J. B.; Venable, R. M.; Freites, J. A.; O’Connor, J. W.; Tobias, D. J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A. D.; Pastor, R. W. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 2010, 114, 7830– 7843,  DOI: 10.1021/jp101759q
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    Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
    Klauda, Jeffery B.; Venable, Richard M.; Freites, J. Alfredo; O'Connor, Joseph W.; Tobias, Douglas J.; Mondragon-Ramirez, Carlos; Vorobyov, Igor; MacKerell, Alexander D., Jr.; Pastor, Richard W.
    Journal of Physical Chemistry B (2010), 114 (23), 7830-7843CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    A significant modification to the additive all-atom CHARMM lipid force field (FF) is developed and applied to phospholipid bilayers with both choline and ethanolamine contg. head groups and with both satd. and unsatd. aliph. chains. Motivated by the current CHARMM lipid FF (C27 and C27r) systematically yielding values of the surface area per lipid that are smaller than exptl. ests. and gel-like structures of bilayers well above the gel transition temp., selected torsional, Lennard-Jones and partial at. charge parameters were modified by targeting both quantum mech. (QM) and exptl. data. QM calcns. ranging from high-level ab initio calcns. on small mols. to semiempirical QM studies on a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer in combination with exptl. thermodn. data were used as target data for parameter optimization. These changes were tested with simulations of pure bilayers at high hydration of the following six lipids: DPPC, 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-phosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2-dioleoyl-sn-phosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-phosphatidylethanolamine (POPE); simulations of a low hydration DOPC bilayer were also performed. Agreement with exptl. surface area is on av. within 2%, and the d. profiles agree well with neutron and x-ray diffraction expts. NMR deuterium order parameters (SCD) are well predicted with the new FF, including proper splitting of the SCD for the aliph. carbon adjacent to the carbonyl for DPPC, POPE, and POPC bilayers. The area compressibility modulus and frequency dependence of 13C NMR relaxation rates of DPPC and the water distribution of low hydration DOPC bilayers also agree well with expt. Accordingly, the presented lipid FF, referred to as C36, allows for mol. dynamics simulations to be run in the tensionless ensemble (NPT), and is anticipated to be of utility for simulations of pure lipid systems as well as heterogeneous systems including membrane proteins.
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  27. 27
    Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983, 79, 926– 935,  DOI: 10.1063/1.445869
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    27
    Comparison of simple potential functions for simulating liquid water
    Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
    Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
    Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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  28. 28
    Brunner, J. D.; Lim, N. K.; Schenck, S.; Duerst, A.; Dutzler, R. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature 2014, 516, 207– 212,  DOI: 10.1038/nature13984
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    28
    X-ray structure of a calcium-activated TMEM16 lipid scramblase
    Brunner, Janine D.; Lim, Novandy K.; Schenck, Stephan; Duerst, Alessia; Dutzler, Raimund
    Nature (London, United Kingdom) (2014), 516 (7530), 207-212CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca2+-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria hematococca that operates as a Ca2+-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helixes and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbors a conserved Ca2+-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca2+ coordination affect both lipid scrambling in N. hematococca TMEM16 and ion conduction in the Cl- channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca2+ activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.
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  29. 29
    Bushell, S. R.; Pike, A. C.; Falzone, M. E.; Rorsman, N. J.; Ta, C. M.; Corey, R. A.; Newport, T. D.; Christianson, J. C.; Scofano, L. F.; Shintre, C. A.; Tessitore, A.; Chu, A.; Wang, Q.; Shrestha, L.; Mukhopadhyay, S. M. M.; Love, J. D.; Burgess-Brown, N. A.; Sitsapesan, R.; Stansfeld, P. J.; Huiskonen, J. T.; Tammaro, P.; Accardi, A.; Carpenter, E. P. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nat. Commun. 2019, 10, 3956  DOI: 10.1038/s41467-019-11753-1
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    29
    The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
    Bushell Simon R; Pike Ashley C W; Shintre Chitra A; Tessitore Annamaria; Chu Amy; Wang Qinrui; Shrestha Leela; Mukhopadhyay Shubhashish M M; Burgess-Brown Nicola A; Carpenter Elisabeth P; Falzone Maria E; Accardi Alessio; Rorsman Nils J G; Ta Chau M; Scofano Lara F; Sitsapesan Rebecca; Tammaro Paolo; Rorsman Nils J G; Ta Chau M; Corey Robin A; Newport Thomas D; Wang Qinrui; Stansfeld Phillip J; Newport Thomas D; Christianson John C; Shintre Chitra A; Tessitore Annamaria; Chu Amy; Love James D; Love James D; Huiskonen Juha T; Accardi Alessio; Accardi Alessio
    Nature communications (2019), 10 (1), 3956 ISSN:.
    Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.
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  30. 30
    Kostritskii, A. Y.; Machtens, J.-P. Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases. Nat. Commun. 2021, in press, DOI: 10.1038/s41467-021-22724-w .
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    Alleva, C.; Kovalev, K.; Astashkin, R.; Berndt, M. I.; Baeken, C.; Balandin, T.; Gordeliy, V.; Fahlke, C.; Machtens, J.-P. Na+-dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters. Sci. Adv. 2020, 6, eaba9854  DOI: 10.1126/sciadv.aba9854
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    Lomize, M. A.; Pogozheva, I. D.; Joo, H.; Mosberg, H. I.; Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 2012, 40, D370– D376,  DOI: 10.1093/nar/gkr703
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    OPM database and PPM web server: resources for positioning of proteins in membranes
    Lomize, Mikhail A.; Pogozheva, Irina D.; Joo, Hyeon; Mosberg, Henry I.; Lomize, Andrei L.
    Nucleic Acids Research (2012), 40 (D1), D370-D376CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The Orientations of Proteins in Membranes (OPM) database is a curated web resource that provides spatial positions of membrane-bound peptides and proteins of known three-dimensional structure in the lipid bilayer, together with their structural classification, topol. and intracellular localization. OPM currently contains more than 1200 transmembrane and peripheral proteins and peptides from approx. 350 organisms that represent approx. 3800 Protein Data Bank entries. Proteins are classified into classes, superfamilies and families and assigned to 21 distinct membrane types. Spatial positions of proteins with respect to the lipid bilayer are optimized by the PPM 2.0 method that accounts for the hydrophobic, hydrogen bonding and electrostatic interactions of the proteins with the anisotropic water-lipid environment described by the dielec. const. and hydrogen-bonding profiles. The OPM database is freely accessible at http://opm.phar.umich.edu. Data can be sorted, searched or retrieved using the hierarchical classification, source organism, localization in different types of membranes. The database offers downloadable coordinates of proteins and peptides with membrane boundaries. A gallery of protein images and several visualization tools are provided. The database is supplemented by the PPM server (http://opm.phar.umich.edu/server.php) which can be used for calcg. spatial positions in membranes of newly detd. proteins structures or theor. models.
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  33. 33
    Lindorff-Larsen, K.; Piana, S.; Palmo, K.; Maragakis, P.; Klepeis, J. L.; Dror, R. O.; Shaw, D. E. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins: Struct., Funct., Bioinf. 2010, 78, 1950– 1958,  DOI: 10.1002/prot.22711
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    Improved side-chain torsion potentials for the Amber ff99SB protein force field
    Lindorff-Larsen, Kresten; Piana, Stefano; Palmo, Kim; Maragakis, Paul; Klepeis, John L.; Dror, Ron O.; Shaw, David E.
    Proteins: Structure, Function, and Bioinformatics (2010), 78 (8), 1950-1958CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)
    Recent advances in hardware and software have enabled increasingly long mol. dynamics (MD) simulations of biomols., exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, the authors further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, the authors used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, the authors optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mech. calcns. Finally, the authors used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of exptl. NMR measurements that directly probe side-chain conformations. The new force field, which the authors have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc.
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  34. 34
    Berger, O.; Edholm, O.; Jähnig, F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys. J. 1997, 72, 2002– 2013,  DOI: 10.1016/S0006-3495(97)78845-3
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    34
    Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature
    Berger, Oliver; Edholm, Olle; Jahnig, Fritz
    Biophysical Journal (1997), 72 (5), 2002-2013CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
    Mol. dynamics simulations of 500 ps were performed on a system consisting of a bilayer of 64 mols. of the lipid dipalmitoylphosphatidylcholine and 23 water mols. per lipid at an isotropic pressure of 1 atm and 50°. Special attention was devoted to reproduce the correct d. of the lipid, because this quantity is known exptl. with a precision better than 1%. For this purpose, the Lennard-Jones parameters of the hydrocarbon chains were adjusted by simulating a system consisting of 128 pentadecane mols. and varying the Lennard-Jones parameters until the exptl. d. and heat of vaporization were obtained. With these parameters the lipid d. resulted in perfect agreement with the exptl. d. The orientational order parameter of the hydrocarbon chains agreed perfectly well with the exptl. values, which, because of its correlation with the area per lipid, makes it possible to give a proper est. of the area per lipid of 0.61±0.1 nm2.
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  35. 35
    Joung, I. S.; Cheatham, T. E. Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations. J. Phys. Chem. B 2008, 112, 9020– 9041,  DOI: 10.1021/jp8001614
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    35
    Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations
    Joung, In Suk; Cheatham, Thomas E.
    Journal of Physical Chemistry B (2008), 112 (30), 9020-9041CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    Alkali (Li+, Na+, K+, Rb+, and Cs+) and halide (F-, Cl-, Br-, and I-) ions play an important role in many biol. phenomena, roles that range from stabilization of biomol. structure, to influence on biomol. dynamics, to key physiol. influence on homeostasis and signaling. To properly model ionic interaction and stability in atomistic simulations of biomol. structure, dynamics, folding, catalysis, and function, an accurate model or representation of the monovalent ions is critically necessary. A good model needs to simultaneously reproduce many properties of ions, including their structure, dynamics, solvation, and moreover both the interactions of these ions with each other in the crystal and in soln. and the interactions of ions with other mols. At present, the best force fields for biomols. employ a simple additive, nonpolarizable, and pairwise potential for at. interaction. In this work, the authors describe their efforts to build better models of the monovalent ions within the pairwise Coulombic and 6-12 Lennard-Jones framework, where the models are tuned to balance crystal and soln. properties in Ewald simulations with specific choices of well-known water models. Although it has been clearly demonstrated that truly accurate treatments of ions will require inclusion of nonadditivity and polarizability (particularly with the anions) and ultimately even a quantum mech. treatment, the authors' goal was to simply push the limits of the additive treatments to see if a balanced model could be created. The applied methodol. is general and can be extended to other ions and to polarizable force-field models. The authors' starting point centered on observations from long simulations of biomols. in salt soln. with the AMBER force fields where salt crystals formed well below their soly. limit. The likely cause of the artifact in the AMBER parameters relates to the naive mixing of the Smith and Dang chloride parameters with AMBER-adapted Aqvist cation parameters. To provide a more appropriate balance, the authors reoptimized the parameters of the Lennard-Jones potential for the ions and specific choices of water models. To validate and optimize the parameters, the authors calcd. hydration free energies of the solvated ions and also lattice energies (LE) and lattice consts. (LC) of alkali halide salt crystals. This is the first effort that systematically scans across the Lennard-Jones space (well depth and radius) while balancing ion properties like LE and LC across all pair combinations of the alkali ions and halide ions. The optimization across the entire monovalent series avoids systematic deviations. The ion parameters developed, optimized, and characterized were targeted for use with some of the most commonly used rigid and nonpolarizable water models, specifically TIP3P, TIP4PEW, and SPC/E. In addn. to well reproducing the soln. and crystal properties, the new ion parameters well reproduce binding energies of the ions to water and the radii of the first hydration shells.
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  36. 36
    Drew, H. R.; Dickerson, R. E. Structure of a B-DNA dodecamer. III. Geometry of hydration. J. Mol. Biol. 1981, 151, 535– 556,  DOI: 10.1016/0022-2836(81)90009-7
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    Structure of a B-DNA dodecamer. III. Geometry of hydration
    Drew, Horace R.; Dickerson, Richard E.
    Journal of Molecular Biology (1981), 151 (3), 535-56CODEN: JMOBAK; ISSN:0022-2836.
    The B-DNA dodecamer, C-G-C-G-A-A-T-T-C-G-C-G, crystd. as slightly more than 1 full turn of right-handed B-DNA in space group P212121 with cell dimensions a = 24.87 Å, b = 40.39 Å, and c = 66.20 Å. X-ray anal. showed that it was surrounded by 72 ordered water mols., mostly assocd. with polar N and O atoms at exposed edges of base-pairs. Hydration in the major groove was mainly in the form of a monodentate monolayer. Hydration of backbone phosphate O atoms were not ordered, except when immobilized by the 5-Me groups of adjacent thymines. The minor groove was extensively and regularly hydrated, with a zigzag spine of 1st- and 2nd-shell hydration along the floor of the groove serving as a foundation for less-regular outer shells extending beyond the radius of the phosphate backbone. The spine network bridged purine N-3 and pyrimidine O-2 atoms in adjacent base pairs; it was regular in the A-A-T-T center, but was disrupted at the C-G-C-G ends, partly by the guanine N-2 amino groups. The minor groove hydration spine may be responsible for the stability of the B form of polymers contg. only A-T and I-C base pairs, and its disruption may explain the ease of transition to the A form of polymers with G-C pairs.
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  37. 37
    Pérez, A.; Marchán, I.; Svozil, D.; Sponer, J.; Cheatham, T. E.; Laughton, C. A.; Orozco, M. Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers. Biophys. J. 2007, 92, 3817– 3829,  DOI: 10.1529/biophysj.106.097782
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    Refinement of the AMBER force field for nucleic acids: improving the description of α/γ conformers
    Perez, Alberto; Marchan, Ivan; Svozil, Daniel; Sponer, Jiri; Cheatham, Thomas E., III; Laughton, Charles A.; Orozco, Modesto
    Biophysical Journal (2007), 92 (11), 3817-3829CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
    We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the α/γ concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the α/γ = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mech. data and verified by comparison with very high-level quantum mech. calcns. and by a very extensive comparison between simulations and exptl. data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 μs of state-of-the-art mol. dynamics simulations in aq. soln.
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  38. 38
    Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 1981, 52, 7182– 7190,  DOI: 10.1063/1.328693
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    Polymorphic transitions in single crystals: A new molecular dynamics method
    Parrinello, M.; Rahman, A.
    Journal of Applied Physics (1981), 52 (12), 7182-90CODEN: JAPIAU; ISSN:0021-8979.
    A Lagrangian formulation is introduced; it can be used to make mol. dynamics (MD) calcns. on systems under the most general, externally applied, conditions of stress. In this formulation the MD cell shape and size can change according to dynamic equations given by this Lagrangian. This MD technique was used to the study of structural transitions of a Ni single crystal under uniform uniaxial compressive and tensile loads. Some results regarding the stress-strain relation obtained by static calcns. are invalid at finite temp. Under compressive loading, the model of Ni shows a bifurcation in its stress-strain relation; this bifurcation provides a link in configuration space between cubic and hexagonal close packing. Such a transition could perhaps be obsd. exptl. under extreme conditions of shock.
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  39. 39
    Kondinskaia, D. A.; Kostritskii, A. Y.; Nesterenko, A. M.; Antipina, A. Y.; Gurtovenko, A. A. Atomic-Scale Molecular Dynamics Simulations of DNA-Polycation Complexes: Two Distinct Binding Patterns. J. Phys. Chem. B 2016, 120, 6546– 6554,  DOI: 10.1021/acs.jpcb.6b03779
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    Atomic-Scale Molecular Dynamics Simulations of DNA-Polycation Complexes: Two Distinct Binding Patterns
    Kondinskaia, Diana A.; Kostritskii, Andrei Yu.; Nesterenko, Alexey M.; Antipina, Alexandra Yu.; Gurtovenko, Andrey A.
    Journal of Physical Chemistry B (2016), 120 (27), 6546-6554CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Synthetic cationic polymers represent a promising class of delivery vectors for gene therapy. Here, we employ atomistic mol. dynamics simulations to gain insight into the structure and properties of complexes of DNA with four linear polycations: polyethylenimine (PEI), poly-L-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). These polycations differ in their polymer geometries, protonation states, and hydrophobicities of their backbone chains. Overall, our results demonstrate for the first time the existence of two distinct patterns of binding of DNA with polycations. For PEI, PLL, and PAA, the complex is stabilized by the electrostatic attraction between protonated amine groups of the polycation and phosphate groups of DNA. In contrast, PVA demonstrates an alternative binding pattern as it gets embedded into the DNA major groove. It is likely that both the polymer topol. and affinity of the backbone chain of PVA to the DNA groove are responsible for such behavior. The differences in binding patterns can have important biomedical implications: embedding PVA into a DNA groove makes it less sensitive to changes in the aq. environment (pH level, ionic strength, etc.) and could therefore hinder the intracellular release of genetic material from a delivery vector, leading to lower transfection activity.
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    Michaud-Agrawal, N.; Denning, E. J.; Woolf, T. B.; Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 2011, 32, 2319– 2327,  DOI: 10.1002/jcc.21787
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    MDAnalysis: A toolkit for the analysis of molecular dynamics simulations
    Michaud-Agrawal, Naveen; Denning, Elizabeth J.; Woolf, Thomas B.; Beckstein, Oliver
    Journal of Computational Chemistry (2011), 32 (10), 2319-2327CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    MDAnal. is an object-oriented library for structural and temporal anal. of mol. dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-crit. code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM's powerful selection commands. MDAnal. enables both novice and experienced programmers to rapidly write their own anal. tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative anal. MDAnal. has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU General Public License from http://mdanal.googlecode.com. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011.
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    North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 2002, 82, 1013– 1067,  DOI: 10.1152/physrev.00015.2002
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    Molecular physiology of P2X receptors
    North, R. Alan
    Physiological Reviews (2002), 82 (4), 1013-1067CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
    A review. P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40-50% identical in amino acid sequence. Each subunit has two transmembrane domains, sepd. by an extracellular domain (∼280 amino acids). Channels form as multimers of several subunits. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X2/3 and P2X1/5 channels have been most fully characterized following heterologous expression. Some agonists (e.g., αβ-methylene ATP) and antagonists [e.g., 2',3'-O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors contg. P2X1 and P2X3 subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7 receptors induces a permeability increase to larger org. cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve addnl. interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The mol. compn. of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X7 receptor activation stimulates cytokine release by engaging intracellular signaling pathways.
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  42. 42
    Surprenant, A.; North, R. A. Signaling at purinergic P2X receptors. Annu. Rev. Physiol. 2009, 71, 333– 359,  DOI: 10.1146/annurev.physiol.70.113006.100630
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    Signaling at purinergic P2X receptors
    Surprenant, Annmarie; North, R. Alan
    Annual Review of Physiology (2009), 71 (), 333-359CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)
    A review. P2X receptors are membrane cation channels gated by extracellular ATP. Seven P2X receptor subunits (P2X1-7) are widely distributed in excitable and nonexcitable cells of vertebrates. They play key roles in inter alia afferent signaling (including pain), regulation of renal blood flow, vascular endothelium, and inflammatory responses. We summarize the evidence for these and other roles, emphasizing exptl. work with selective receptor antagonists or with knockout mice. The receptors are trimeric membrane proteins: studies of the biophys. properties of mutated subunits expressed in heterologous cells have indicated parts of the subunits involved in ATP binding, ion permeation (including calcium permeability), and membrane trafficking. We review our current understanding of the mol. properties of P2X receptors, including how this understanding is informed by the identification of distantly related P2X receptors in simple eukaryotes.
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    Illes, P.; Müller, C. E.; Jacobson, K. A.; Grutter, T.; Nicke, A.; Fountain, S. J.; Kennedy, C.; Schmalzing, G.; Jarvis, M. F.; Stojilkovic, S. S. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Br. J. Pharmacol. 2021, 178, 489– 514,  DOI: 10.1111/bph.15299
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    Update of P2X receptor properties and their pharmacology: IUPHAR Review 30
    Illes, Peter; Mueller, Christa E.; Jacobson, Kenneth A.; Grutter, Thomas; Nicke, Annette; Fountain, Samuel J.; Kennedy, Charles; Schmalzing, Guenther; Jarvis, Michael F.; Stojilkovic, Stanko S.; King, Brian F.; Di Virgilio, Francesco
    British Journal of Pharmacology (2021), 178 (3), 489-514CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
    A review. The known seven mammalian receptor subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystn. allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighboring subunits. In addn. to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chem. supplied a range of subtype-selective antagonists, as well as pos. and neg. allosteric modulators. Knockout mice and selective antagonists helped to identify pathol. functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).
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    Briones, R.; Blau, C.; Kutzner, C.; de Groot, B. L.; Aponte-Santamaría, C. Gromaρs: A Gromacs-Based Toolset to Analyse Density Maps Derived from Molecular Dynamics Simulations. Biophys. J. 2019, 116, 4– 11,  DOI: 10.1016/j.bpj.2018.11.3126
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    GROmaρs: A GROMACS-Based Toolset to Analyze Density Maps Derived from Molecular Dynamics Simulations
    Briones, Rodolfo; Blau, Christian; Kutzner, Carsten; de Groot, Bert L.; Aponte-Santamaria, Camilo
    Biophysical Journal (2019), 116 (1), 4-11CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    The authors introduce a computational toolset, named GROmaρs, to obtain and compare time-averaged d. maps from mol. dynamics simulations. GROmaρs efficiently computes d. maps by fast multi-Gaussian spreading of at. densities onto a three-dimensional grid. It complements existing map-based tools by enabling spatial inspection of at. av. localization during the simulations. Most importantly, it allows the comparison between computed and ref. maps (e.g., exptl.) through calcn. of difference maps and local and time-resolved global correlation. These comparison operations proved useful to quant. contrast perturbed and control simulation data sets and to examine how much biomol. systems resemble both synthetic and exptl. d. maps. This was esp. advantageous for multimol. systems in which std. comparisons like RMSDs are difficult to compute. In addn., GROmaρs incorporates abs. and relative spatial free-energy ests. to provide an energetic picture of atomistic localization. This is an open-source GROMACS-based toolset, thus allowing for static or dynamic selection of atoms or even coarse-grained beads for the d. calcn. Furthermore, masking of regions was implemented to speed up calcns. and to facilitate the comparison with exptl. maps. Beyond map comparison, GROmaρs provides a straightforward method to detect solvent cavities and av. charge distribution in biomol. systems. The authors employed all these functionalities to inspect the localization of lipid and water mols. in aquaporin systems, the binding of cholesterol to the G protein coupled chemokine receptor type 4, and the identification of permeation pathways through the dermicidin antimicrobial channel. Based on these examples, the authors anticipate a high applicability of GROmaρs for the anal. of mol. dynamics simulations and their comparison with exptl. detd. densities.
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    Chen, X.; Bründl, M.; Friesacher, T.; Stary-Weinzinger, A. Computational Insights Into Voltage Dependence of Polyamine Block in a Strong Inwardly Rectifying K+ Channel. Front. Pharmacol. 2020, 11, 721  DOI: 10.3389/fphar.2020.00721
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    Computational insights into voltage dependence of polyamine block in a strong inwardly rectifying K+ channel
    Chen, Xingyu; Bruendl, Michael; Friesacher, Theres; Stary-Weinzinger, Anna
    Frontiers in Pharmacology (2020), 11 (), 00721CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
    Inwardly rectifying potassium (KIR) channels play important roles in controlling cellular excitability and K+ ion homeostasis. Under physiol. conditions, KIR channels allow large K+ influx at potentials neg. to the equil. potential of K+ but permit little outward current at potentials pos. to the equil. potential of K+, due to voltage dependent block of outward K+ flux by cytoplasmic polyamines. These polycationic mols. enter the KIR channel pore from the intracellular side. They block K+ ion movement through the channel at depolarized potentials, thereby ensuring, for instance, the long plateau phase of the cardiac action potential. Key questions concerning how deeply these charged mols. migrate into the pore and how the steep voltage dependence arises remain unclear. Recent MD simulations on GIRK2 (=Kir3.2) crystal structures have provided unprecedented details concerning the conduction mechanism of a KIR channel. Here, we use MD simulations with applied field to provide detailed insights into voltage dependent block of putrescine, using the conductive state of the strong inwardly rectifying K+ channel GIRK2 as starting point. Our μs long simulations elucidate details about binding sites of putrescine in the pore and suggest that voltage dependent rectification arises from a dual mechanism.
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    Nyblom, M.; Frick, A.; Wang, Y.; Ekvall, M.; Hallgren, K.; Hedfalk, K.; Neutze, R.; Tajkhorshid, E.; Törnroth-Horsefield, S. Structural and functional analysis of SoPIP2;1 mutants adds insight into plant aquaporin gating. J. Mol. Biol. 2009, 387, 653– 668,  DOI: 10.1016/j.jmb.2009.01.065
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    Structural and Functional Analysis of SoPIP2;1 Mutants Adds Insight into Plant Aquaporin Gating
    Nyblom, Maria; Frick, Anna; Wang, Yi; Ekvall, Mikael; Hallgren, Karin; Hedfalk, Kristina; Neutze, Richard; Tajkhorshid, Emad; Toernroth-Horsefield, Susanna
    Journal of Molecular Biology (2009), 387 (3), 653-668CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
    Plant plasma membrane aquaporins facilitate water flux into and out of plant cells, thus coupling their cellular function to basic aspects of plant physiol. Posttranslational modifications of conserved phosphorylation sites, changes in cytoplasmic pH, and the binding of Ca2+ can regulate water transport activity by gating the plasma membrane aquaporins. A structural mechanism unifying these diverse biochem. signals has emerged for the spinach aquaporin SoPIP2;1, although several questions concerning the opening mechanism remain. Here, we describe the X-ray structures of the S115E and S274E single SoPIP2;1 mutants and the corresponding double mutant. Phosphorylation of these serines is believed to increase water transport activity of SoPIP2;1 by opening the channel. However, all mutants crystd. in a closed conformation, as confirmed by water transport assays, implying that neither substitution fully mimics the phosphorylated state. Nevertheless, a half-turn extension of transmembrane helix 1 occurs upon the substitution of Ser115, which draws the Cα atom of Glu31 10 Å away from its wild-type conformation, thereby disrupting the divalent cation binding site involved in the gating mechanism. Mutation of Ser274 disorders the C-terminus but no other significant conformational changes are obsd. Inspection of the hydrogen-bond interactions within loop D suggested that the phosphorylation of Ser188 may also produce an open channel, and this was supported by an increased water transport activity for the S188E mutant and mol. dynamics simulations. These findings add addnl. insight into the general mechanism of plant aquaporin gating.
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    Ruiz, L.; Wu, Y.; Keten, S. Tailoring the water structure and transport in nanotubes with tunable interiors. Nanoscale 2015, 7, 121– 132,  DOI: 10.1039/C4NR05407E
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    Tailoring the water structure and transport in nanotubes with tunable interiors
    Ruiz, Luis; Wu, Yuanqiao; Keten, Sinan
    Nanoscale (2015), 7 (1), 121-132CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Self-assembly of cyclic peptide nanotubes (CPNs) in polymer thin films has opened up the possibility of creating sepn. membranes with tunable nanopores that can differentiate mols. at the sub-nanometer level. While it has been demonstrated that the interior chem. of the CPNs can be tailored by inserting functional groups in the nanopore lumen (mCPNs), a design strategy for picking the chem. modifications that lead to particular transport properties has not been established. Drawing from the knowledgebase of functional groups in natural amino acids, here we use mol. dynamics simulations to elucidate how bioinspired mutations influence the transport of water through mCPNs. We show that, at the nanoscale, factors besides the pore size, such as electrostatic interactions and steric effects, can dramatically change the transport properties. We recognize a novel asym. structure of water under nanoconfinement inside the chem. functionalized nanotubes and identify that the small non-polar glycine-mimic groups that minimize the steric constraints and confer a hydrophobic character to the nanotube interior are the fastest transporters of water. Our computationally developed expts. on a realistic material system circumvent synthetic challenges, and lay the foundation for bioinspired principles to tailor artificial nanochannels for sepn. applications such as desalination, ion-exchange and carbon capture.
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    Kasimova, M. A.; Lindahl, E.; Delemotte, L. Determining the molecular basis of voltage sensitivity in membrane proteins. J. Gen. Physiol. 2018, 150, 1444– 1458,  DOI: 10.1085/jgp.201812086
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    Determining the molecular basis of voltage sensitivity in membrane proteins
    Kasimova, Marina A.; Lindahl, Erik; Delemotte, Lucie
    Journal of General Physiology (2018), 150 (10), 1444-1458CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
    Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mech. work. They are responsible for a spectrum of physiol. processes in living organisms, including elec. signaling and cell-cycle progression. Moreover, the detection of these elements by using exptl. techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estn. of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis expts. will significantly reduce the no. of potential voltage-sensitive elements to be tested.
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    Scheurer, M.; Rodenkirch, P.; Siggel, M.; Bernardi, R. C.; Schulten, K.; Tajkhorshid, E.; Rudack, T. PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations. Biophys. J. 2018, 114, 577– 583,  DOI: 10.1016/j.bpj.2017.12.003
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    PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations
    Scheurer, Maximilian; Rodenkirch, Peter; Siggel, Marc; Bernardi, Rafael C.; Schulten, Klaus; Tajkhorshid, Emad; Rudack, Till
    Biophysical Journal (2018), 114 (3), 577-583CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    Mol. dynamics (MD) simulations have become ubiquitous in all areas of life sciences. The size and model complexity of MD simulations are rapidly growing along with increasing computing power and improved algorithms. This growth gave a large amt. of simulation data that need to be filtered for relevant information to address specific biomedical and biochem. questions. One of the most relevant mol. properties that can be studied by all-atom MD simulations is the time-dependent evolution of the complex noncovalent interaction networks governing such fundamental aspects as mol. recognition, binding strength, and mech. and structural stability. Extg., evaluating, and visualizing noncovalent interactions is a key task in the daily work of structural biologists. The authors have developed PyContact, an easy-to-use, highly flexible, and intuitive graphical user interface-based application, designed to provide a toolkit to study biomol. interactions in MD trajectories. PyContact is designed to facilitate this task by enabling identification of relevant noncovalent interactions in a comprehensible manner. The implementation of PyContact as a standalone application enables rapid anal. and data visualization without any addnl. programming requirements, and also preserves full in-program customization and extension capabilities for advanced users. The statistical anal. representation is interactively combined with full mapping of the results on the mol. system through the synergistic connection between PyContact and VMD. The authors showcase the capabilities and scientific significance of PyContact by analyzing and visualizing in great detail the noncovalent interactions underlying the ion permeation pathway of the human P2X3 receptor. As a second application, the authors examine the protein-protein interaction network of the mech. ultrastable cohesin-dockering complex.
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    Melcr, J.; Martinez-Seara, H.; Nencini, R.; Kolafa, J.; Jungwirth, P.; Ollila, O. H. S. Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization. J. Phys. Chem. B 2018, 122, 4546– 4557,  DOI: 10.1021/acs.jpcb.7b12510
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    Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization
    Melcr, Josef; Martinez-Seara, Hector; Nencini, Ricky; Kolafa, Jiri; Jungwirth, Pavel; Ollila, O. H. Samuli
    Journal of Physical Chemistry B (2018), 122 (16), 4546-4557CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Binding affinities and stoichiometries of Na+ and Ca2+ ions to phospholipid bilayers are of paramount significance in the properties and functionality of cellular membranes. Current ests. of binding affinities and stoichiometries of cations are, however, inconsistent due to limitations in the available exptl. and computational methods. In this work, the authors improve the description of the binding details of Na+ and Ca2+ ions to a 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) bilayer by implicitly including electronic polarization as a mean field correction, known as the electronic continuum correction (ECC). This is applied by scaling the partial charges of a selected state-of-the-art POPC lipid model for mol. dynamics simulations. The improved ECC-POPC model reproduces not only the exptl. measured structural parameters for the ion-free membrane, but also the response of lipid headgroup to a strongly bound cationic amphiphile, as well as the binding affinities of Na+ and Ca2+ ions. With the new model, the authors observe on the one side negligible binding of Na+ ions to POPC bilayer, while on the other side stronger interactions of Ca2+ primarily with phosphate oxygens, which is in agreement with the previous interpretations of the exptl. spectroscopic data. The present model results in Ca2+ ions forming complexes with one to three POPC mols. with almost equal probabilities, suggesting more complex binding stoichiometries than those from simple models used to interpret the NMR data previously. The results of this work pave the way to quant. mol. simulations with realistic electrostatic interactions of complex biochem. systems at cellular membranes.
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    Melcrová, A.; Pokorna, S.; Pullanchery, S.; Kohagen, M.; Jurkiewicz, P.; Hof, M.; Jungwirth, P.; Cremer, P. S.; Cwiklik, L. The complex nature of calcium cation interactions with phospholipid bilayers. Sci. Rep. 2016, 6, 38035  DOI: 10.1038/srep38035
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    The complex nature of calcium cation interactions with phospholipid bilayers
    Melcrova, Adela; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz
    Scientific Reports (2016), 6 (), 38035CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    Understanding interactions of calcium with lipid membranes at the mol. level is of great importance in light of their involvement in calcium signaling, assocn. of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic mol. dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-contg. environments. To gain addnl. at.-level information, the expts. are complemented by mol. simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concn. with important implications for calcium buffering, synaptic plasticity, and protein-membrane assocn.
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    Burnstock, G. Purinergic signalling and disorders of the central nervous system. Nat. Rev. Drug Discovery 2008, 7, 575– 590,  DOI: 10.1038/nrd2605
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    Purinergic signaling and disorders of the central nervous system
    Burnstock, Geoffrey
    Nature Reviews Drug Discovery (2008), 7 (7), 575-590CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. There is increasing interest in the role of purinergic signaling in CNS disorders, but few modulators have reached the clinic. Here, Burnstock provides an overview of the role of purinergic signaling in specific disorders, including brain trauma, ischemia, neurodegenerative, neuroinflammatory and neuropsychiatric diseases, and highlights specific purinergic receptor subtypes that represent promising therapeutic targets. Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathol. conditions including brain trauma and ischemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signaling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A2A, P2X4 and P2X7, that might be therapeutically targeted for the treatment of these conditions.
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    Pomorski, T.; Menon, A. K. Lipid flippases and their biological functions. Cell. Mol. Life Sci. 2006, 63, 2908– 2921,  DOI: 10.1007/s00018-006-6167-7
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    Lipid flippases and their biological functions
    Pomorski, T.; Menon, A. K.
    Cellular and Molecular Life Sciences (2006), 63 (24), 2908-2921CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
    A review. The typically distinct phospholipid compn. of the 2 leaflets of a membrane bilayer is generated and maintained by bi-directional transport (flip-flop) of lipids between the leaflets. Specific membrane proteins, termed lipid flippases, play an essential role in this transport process. Energy-independent flippases allow common phospholipids to equilibrate rapidly between the two monolayers and also play a role in the biosynthesis of a variety of glycoconjugates such as glycosphingolipids, N-glycoproteins, and glycosylphosphatidylinositol (GPI)-anchored proteins. ATP-dependent flippases, including members of a conserved subfamily of P-type ATPases and ATP-binding cassette transporters, mediate the net transfer of specific phospholipids to one leaflet of a membrane and are involved in the creation and maintenance of transbilayer lipid asymmetry of membranes such as the plasma membrane of eukaryotes. Energy-dependent flippases also play a role in the biosynthesis of glycoconjugates such as bacterial lipopolysaccharide. Here, the authors summarize recent progress on the identification and characterization of the various flippases and the demonstration of their biol. functions.
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    Jiang, T.; Yu, K.; Hartzell, H. C.; Tajkhorshid, E. Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase. eLife 2017, 6, e28671  DOI: 10.7554/eLife.28671
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    Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase
    Jiang, Tao; Yu, Kuai; Hartzell, H. Criss; Tajkhorshid, Emad
    eLife (2017), 6 (), e28671/1-e28671/26CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
    From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with exptl. assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helixes that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase.
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    Bethel, N. P.; Grabe, M. Atomistic insight into lipid translocation by a TMEM16 scramblase. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 14049– 14054,  DOI: 10.1073/pnas.1607574113
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    Atomistic insight into lipid translocation by a TMEM16 scramblase
    Bethel, Neville P.; Grabe, Michael
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (49), 14049-14054CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The transmembrane protein 16 (TMEM16) family of membrane proteins includes both lipid scramblases and ion channels involved in olfaction, nociception, and blood coagulation. The crystal structure of the fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase suggested a putative mechanism of lipid transport, whereby polar and charged lipid headgroups move through the low-dielec. environment of the membrane by traversing a hydrophilic groove on the membrane-spanning surface of the protein. Here, we use computational methods to explore the membrane-protein interactions involved in lipid scrambling. Fast, continuum membrane-bending calcns. reveal a global pattern of charged and hydrophobic surface residues that bends the membrane in a large-amplitude sinusoidal wave, resulting in bilayer thinning across the hydrophilic groove. Atomic simulations uncover two lipid headgroup-interaction sites flanking the groove. The cytoplasmic site nucleates headgroup-dipole stacking interactions that form a chain of lipid mols. that penetrate into the groove. In two instances, a cytoplasmic lipid interdigitates into this chain, crosses the bilayer, and enters the extracellular leaflet, and the reverse process happens twice as well. Continuum membrane-bending anal. carried out on homol. models of mammalian homologs shows that these family members also bend the membrane-even those that lack scramblase activity. Sequence alignments show that the lipid-interaction sites are conserved in many family members but less so in those with reduced scrambling ability. Our anal. provides insight into how large-scale membrane bending and protein chem. facilitate lipid permeation in the TMEM16 family, and we hypothesize that membrane interactions also affect ion permeation.
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  56. 56
    Pedemonte, N.; Galietta, L. J. V. Structure and function of TMEM16 proteins (anoctamins). Physiol. Rev. 2014, 94, 419– 459,  DOI: 10.1152/physrev.00039.2011
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    56
    Structure and function of TMEM16 proteins (anoctamins)
    Pedemonte, Nicoletta; Galietta, Luis J. V.
    Physiological Reviews (2014), 94 (2), 419-459CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
    A review. TMEM16 proteins, also known as anoctamins, are involved in a variety of functions that include ion transport, phospholipid scrambling, and regulation of other membrane proteins. The first two members of the family, TMEM16A (anoctamin-1, AN01) and TMEM16B (anoctamin-2, AN02), function as Ca2+-activated Cl- channels (CaCCs), a type of ion channel that plays important functions such as transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception, and control of neuronal excitability. Genetic ablation of TMEM16A in mice causes impairment of epithelial Cl- secretion, tracheal abnormalities, and block of gastrointestinal peristalsis. TMEM16A is directly regulated by cytosolic Ca2+ as well as indirectly by its interaction with calmodulin. Other members of the anoctamin family, such as TMEM16C, TMEM16D, TMEM16F, TMEM16G, and TMEM16J, may work as phospholipid scramblases and/or ion channels. In particular, TMEM16F (AN06) is a major contributor to the process of phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane. Intriguingly, TMEM16F is also assocd. with the appearance of anion/cation channels activated by very high Ca2+ concns. Furthermore, a TMEM16 protein expressed in Aspergillus fumigatus displays both ion channel and lipid scramblase activity. This finding suggests that dual function is an ancestral characteristic of TMEM16 proteins and that some members, such as TMEM16A and TMEM16B, have evolved to a pure channel function. Mutations in anoctamin genes (AN03, AN05, AN06, and AN010) cause various genetic diseases. These diseases suggest the involvement of anoctamins in a variety of cell functions whose link with ion transport and/or lipid scrambling needs to be clarified.
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  57. 57
    Kalienkova, V.; Clerico Mosina, V.; Bryner, L.; Oostergetel, G. T.; Dutzler, R.; Paulino, C. Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM. eLife 2019, 8, e44364  DOI: 10.7554/eLife.44364
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    57
    Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo- EM
    Kalienkova, Valeria; Mosina, Vanessa Clerico; Bryner, Laura; Oostergetel, Gert T.; Dutzler, Raimund; Paulino, Cristina
    eLife (2019), 8 (), 44364CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
    Scramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca2+ binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca2+-bound state. Addnl., our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.
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    Falzone, M. E.; Rheinberger, J.; Lee, B.-C.; Peyear, T.; Sasset, L.; Raczkowski, A. M.; Eng, E. T.; Di Lorenzo, A.; Andersen, O. S.; Nimigean, C. M.; Accardi, A. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. eLife 2019, 8, e43229  DOI: 10.7554/eLife.43229
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    58
    Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase
    Falzone, Maria E.; Rheinberger, Jan; Lee, Byoung-Cheol; Peyear, Thasin; Sasset, Linda; Raczkowski, Ashleigh M.; Eng, Edward T.; Lorenzo, Annarita Di; Andersen, Olaf S.; Nimigean, Crina M.; Accardi, Alessio
    eLife (2019), 8 (), 43229CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
    The lipid distribution of plasma membranes of eukaryotic cells is asym. and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concn. gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resoln. cryo-electron microscopy structures of a fungal scramblase from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional expts., suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.
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    Feng, S.; Dang, S.; Han, T. W.; Ye, W.; Jin, P.; Cheng, T.; Li, J.; Jan, Y. N.; Jan, L. Y.; Cheng, Y. Cryo-EM studies of TMEM16F Calcium-Activated ion channel suggest features important for lipid scrambling. Cell Rep. 2019, 28, 567– 579,  DOI: 10.1016/j.celrep.2019.06.023
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    59
    Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling
    Feng, Shengjie; Dang, Shangyu; Han, Tina Wei; Ye, Wenlei; Jin, Peng; Cheng, Tong; Li, Junrui; Jan, Yuh Nung; Jan, Lily Yeh; Cheng, Yifan
    Cell Reports (2019), 28 (2), 567-579.e4CODEN: CREED8; ISSN:2211-1247. (Cell Press)
    As a Ca2+-activated lipid scramblase and ion channel that mediates Ca2+ influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca2+ influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest sep. pathways for lipid scrambling and ion permeation.
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    Alvadia, C.; Lim, N. K.; Clerico Mosina, V.; Oostergetel, G. T.; Dutzler, R.; Paulino, C. Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. eLife 2019, 8, e44365  DOI: 10.7554/eLife.44365
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    60
    Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F
    Alvadia, Carolina; Lim, Novandy K.; Mosina, Vanessa Clerico; Oostergetel, Gert T.; Dutzler, Raimund; Paulino, Cristina
    eLife (2019), 8 (), 44365CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
    The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca2+ define the ligand-free closed conformation of the protein and the structure of a Ca2+-bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A, yet with distinct differences in the region of ion and lipid permeation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, both functions appear to be mediated by alternate protein conformations that are at equil. in the ligand-bound state.
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    Lim, N. K.; Lam, A. K.; Dutzler, R. Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A. J. Gen. Physiol. 2016, 148, 375– 392,  DOI: 10.1085/jgp.201611650
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    61
    Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A
    Lim, Novandy K.; Lam, Andy K. M.; Dutzler, Raimund
    Journal of General Physiology (2016), 148 (5), 375-392, S19-S20CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
    The TMEM16 proteins constitute a family of membrane proteins with unusual functional breadth, including lipid scramblases and Cl- channels. Members of both these branches are activated by Ca2+, acting from the intracellular side, and probably share a common architecture, which was defined in the recent structure of the lipid scramblase nhTMEM16. The structural features of subunits and the arrangement of Ca2+-binding sites in nhTMEM16 suggest that the dimeric protein harbors two locations for catalysis that are independent with respect to both activation and lipid conduction. Here, we ask whether a similar independence is obsd. in the Ca2+-activated Cl- channel TMEM16A. For this purpose, we generated concatenated constructs contg. subunits with distinct activation and permeation properties. Our biochem. investigations demonstrate the integrity of concatemers after solubilization and purifn. During investigation by patch-clamp electrophysiol., the functional behavior of constructs contg. either two wild-type (WT) subunits or one WT subunit paired with a second subunit with compromised activation closely resembles TMEM16A. This resemblance extends to ion selectivity, conductance, and the concn. and voltage dependence of channel activation by Ca2+. Constructs combining subunits with different potencies for Ca2+ show a biphasic activation curve that can be described as a linear combination of the properties of its constituents. The functional independence is further supported by mutation of a putative pore-lining residue that changes the conduction properties of the mutated subunit. Our results strongly suggest that TMEM16A contains two ion conduction pores that are independently activated by Ca2+ binding to sites that are embedded within the transmembrane part of each subunit.
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    Jeng, G.; Aggarwal, M.; Yu, W.-P.; Chen, T.-Y. Independent activation of distinct pores in dimeric TMEM16A channels. J. Gen. Physiol. 2016, 148, 393– 404,  DOI: 10.1085/jgp.201611651
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    62
    Independent activation of distinct pores in dimeric TMEM16A channels
    Jeng, Grace; Aggarwal, Muskaan; Yu, Wei-Ping; Chen, Tsung-Yu
    Journal of General Physiology (2016), 148 (5), 393-404, S13-S14CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
    The TMEM16 family encompasses Ca2+-activated Cl- channels (CaCCs) and lipid scramblases. These proteins are formed by two identical subunits, as confirmed by the recently solved crystal structure of a TMEM16 lipid scram-blase. However, the high-resoln. structure did not provide definitive information regarding the pore architecture of the TMEM16 channels. In this study, we express TMEM16A channels constituting two covalently linked subunits with different Ca2+ affinities. The dose-response curve of the heterodimer appears to be a weighted sum of two dose-response curves-one corresponding to the high-affinity subunit and the other to the low-affinity subunit. However, fluorescence resonance energy transfer expts. suggest that the covalently linked heterodimeric proteins fold and assemble as one mol. Together these results suggest that activation of the two TMEM16A subunits likely activate independently of each other. The Ca2+ activation curve for the heterodi-mer at a low Ca2+ concn. range ([Ca2+] < 5μM) is similar to that of the wild-type channel-the Hill coeffs. in both cases are significantly greater than one. This suggests that Ca2+ binding to one subunit of TMEM16A is sufficient to activate the channel and that each subunit contains more than one Ca2+-binding site. We also take advantage of the I-V curve rectification that results from mutation of a pore residue to address the pore architec-ture of the channel. By introducing the pore mutation and the mutation that alters Ca2+ affinity in the same or different subunits, we demonstrate that activation of different subunits appears to be assocd. with the opening of different pores. These results suggest that the TMEM16A CaCC may also adopt a"double-barrel"pore architecture, similar to that found in CLC channels and transporters.
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    Kanner, B. I.; Bendahan, A. Binding order of substrates to the (sodium + potassium ion)-coupled L-glutamic acid transporter from rat brain. Biochemistry 1982, 21, 6327– 6330,  DOI: 10.1021/bi00267a044
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    Binding order of substrates to the (sodium + potassium ion)-coupled L-glutamic acid transporter from rat brain
    Kanner, Baruch I.; Bendahan, Annie
    Biochemistry (1982), 21 (24), 6327-30CODEN: BICHAW; ISSN:0006-2960.
    Efflux of L-glutamic acid (I) [7440-23-5] from rat brain synaptic plasm membrane vesicles requires external K+. This requirement is satd. by concns. of ∼15 mequiv/L K+. In the absence of K+, I can be released from the vesicles in the presence of external I. This stimulation does not require external Na+ but is dependent on the external concn. of I. Half-maximal effects are obtained by concns. of ∼1 μM which are very similar to the apparent Km for I influx. Efflux of labeled I driven by external Na+ plus I requires internal Na+. The transporter apparently displays an asym. behavior toward Na+. This ion dissocs. much more slowly than does I on the external surface of the membrane but not on the internal surface. Furthermore, the transporter apparently translocates K+ in a step distinct from the I translocation step. The simplest explanation is that upon translocation of Na+ and I and their release to the inside, K+ binds to the transporter, enabling it to return to the outside to allow initiation of a new transport cycle.
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    Zerangue, N.; Kavanaugh, M. P. Flux coupling in a neuronal glutamate transporter. Nature 1996, 383, 634– 637,  DOI: 10.1038/383634a0
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    Flux coupling in a neuronal glutamate transporter
    Zerangue, Noa; Kavanaugh, Michael P.
    Nature (London) (1996), 383 (6601), 634-637CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
    Synaptic transmission is commonly terminated by diffusion and reuptake of neurotransmitter from the synaptic cleft. Glutamate reuptake prevents neurotoxicity and sets the lower limit for the concn. of extracellular glutamate, so it is important to understand the thermodn. of this process. Here we use voltage clamping with a pH-sensitive fluorescent dye to monitor elec. currents and pH changes assocd. with flux of glutamate mediated by the human neuronal glutamate transporter EAAT3. In contrast to a previous model, we find that three sodium ions and one proton are cotransported with each glutamate ion into the cell, while one potassium ion is transported out of the cell. This coupling can support a transmembrane glutamate concn. gradient ([Glu]in/[Glu]out) exceeding 106 under equil. conditions, and would allow the transporter to continue removing glutamate over a wide range of ionic conditions.
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    Vandenberg, R. J.; Ryan, R. M. Mechanisms of Glutamate Transport. Physiol. Rev. 2013, 93, 1621– 1657,  DOI: 10.1152/physrev.00007.2013
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    Mechanisms of glutamate transport
    Vandenberg, Robert J.; Ryan, Renae M.
    Physiological Reviews (2013), 93 (4), 1621-1657CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
    A review. L-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurol. disorders. The control of glutamate concns. is crit. to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concns. to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystd. and its structure detd. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.
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    Machtens, J.-P.; Kortzak, D.; Lansche, C.; Leinenweber, A.; Kilian, P.; Begemann, B.; Zachariae, U.; Ewers, D.; de Groot, B. L.; Briones, R.; Fahlke, C. Mechanisms of anion conduction by coupled glutamate transporters. Cell 2015, 160, 542– 553,  DOI: 10.1016/j.cell.2014.12.035
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    Mechanisms of anion conduction by coupled glutamate transporters
    Machtens, Jan-Philipp; Kortzak, Daniel; Lansche, Christine; Leinenweber, Ariane; Kilian, Petra; Begemann, Birgit; Zachariae, Ulrich; Ewers, David; de Groot, Bert L.; Briones, Rodolfo; Fahlke, Christoph
    Cell (Cambridge, MA, United States) (2015), 160 (3), 542-553CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Excitatory amino acid transporters (EAATs) are essential for terminating glutamatergic synaptic transmission. They are not only coupled glutamate/Na+/H+/K+ transporters, but they also function as anion-selective channels. EAAT anion channels regulate neuronal excitability, and gain-of-function mutations in these proteins result in ataxia and epilepsy. Here, the authors combined mol. dynamics simulations with fluorescence spectroscopy of prokaryotic homolog glutamate transporter GltPh and patch-clamp recordings of mammalian EAATs to det. how these transporters conduct anions. Whereas outward- and inward-facing GltPh conformations were nonconductive, lateral movement of the glutamate transport domain from intermediate transporter conformations resulted in the formation of an anion-selective conduction pathway. Fluorescence quenching of inserted Trp residues indicated the entry of anions into this pathway, and mutations of homologous pore-forming residues had analogous effects on GltPh simulations and EAAT2/EAAT4 measurements of single-channel currents and anion/cation selectivities. These findings provided a mechanistic framework of how neurotransmitter transporters can operate as anion-selective and ligand-gated ion channels.
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    Bastug, T.; Heinzelmann, G.; Kuyucak, S.; Salim, M.; Vandenberg, R. J.; Ryan, R. M. Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1. PLoS One 2012, 7, e33058  DOI: 10.1371/journal.pone.0033058
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    Position of the third Na+ site in the Aspartate transporter GltPh and the human glutamate transporter, EAAT1
    Bastug, Turgut; Heinzelmann, Germano; Kuyucak, Serdar; Salim, Marietta; Vandenberg, Robert J.; Ryan, Renae M.
    PLoS One (2012), 7 (3), e33058CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na+ ions, one H+ and the counter-transport of one K+ ion. Transport by an archaeal homolog of the human glutamate transporters, GltPh, whose three dimensional structure is known is also coupled to three Na+ ions but only two Na+ ion binding sites have been obsd. in the crystal structure of GltPh. In order to fully utilize the GltPh structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of GltPh and accurately det. the no. and location of Na+ ions coupled to transport. Several sites have been proposed for the binding of a third Na+ ion from electrostatic calcns. and mol. dynamics simulations. In this study, we have performed detailed free energy simulations for GltPh and reveal a new site for the third Na+ ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in GltPh, and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na+ compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na+ ion in GltPh and EAAT1.
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    Kortzak, D.; Alleva, C.; Weyand, I.; Ewers, D.; Zimmermann, M. I.; Franzen, A.; Machtens, J.-P.; Fahlke, C. Allosteric gate modulation confers K+ coupling in glutamate transporters. EMBO J. 2019, 38, e101468  DOI: 10.15252/embj.2019101468
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    Setiadi, J.; Kuyucak, S. Free-Energy Simulations Resolve the Low-Affinity Na+-High-Affinity Asp Binding Paradox in GltPh. Biophys. J. 2019, 117, 780– 789,  DOI: 10.1016/j.bpj.2019.07.016
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    Free-Energy Simulations Resolve the Low-Affinity Na+-High-Affinity Asp Binding Paradox in GltPh
    Setiadi, Jeffry; Kuyucak, Serdar
    Biophysical Journal (2019), 117 (4), 780-789CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    Glutamate transporters clear up excess extracellular glutamate by cotransporting three Na+ and one H+ with the countertransport of one K+. The archaeal homologs are selective to aspartate and only cotransport three Na+. The crystal structures of GltPh from archaea have been used in computational studies to understand the transport mechanism. Although some progress has been made with regard to the ligand-binding sites, a consistent picture of transport still eludes us. A major concern is the discrepancy between the computed binding free energies, which predict high-affinity Na+-low-affinity aspartate binding, and the exptl. results in which the opposite is obsd. Here, we show that the binding of the first two Na+ ions involves an intermediate state near the Na1 site, where two Na+ ions coexist and couple to aspartate with similar strengths, boosting its affinity. Binding free energies for Na+ and aspartate obtained using this intermediate state are in good agreement with the exptl. values. Thus, the paradox in binding affinities arises from the assumption that the ligands bind to the sites obsd. in the crystal structure following the order dictated by their binding free energies with no intermediate states. In fact, the presence of an intermediate state eliminates such a correlation between the binding free energies and the binding order. The intermediate state also facilitates transition of the first Na+ ion to its final binding site via a knock-on mechanism, which induces substantial conformational changes in the protein consistent with exptl. observations.
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    Machtens, J.-P.; Briones, R.; Alleva, C.; de Groot, B. L.; Fahlke, C. Gating Charge Calculations by Computational Electrophysiology Simulations. Biophys. J. 2017, 112, 1396– 1405,  DOI: 10.1016/j.bpj.2017.02.016
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    Gating Charge Calculations by Computational Electrophysiology Simulations
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    Biophysical Journal (2017), 112 (7), 1396-1405CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
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    Langmuir (2016), 32 (40), 10402-10414CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Although synthetic cationic polymers represent a promising class of effective antibacterial agents, the mol. mechanisms behind their antimicrobial activity remain poorly understood. To this end, we employ at.-scale mol. dynamics simulations to explore adsorption of several linear cationic polymers of different chem. structure and protonation (polyallylamine (PAA), polyethylenimine (PEI), polyvinylamine (PVA) and poly-L-lysine (PLL)) on model bacterial membranes (4:1 mixt. of zwitterionic phosphatidylethanolamine (PE) and anionic phosphatidylglycerol (PG) lipids). Overall, our findings show that binding of polycations to the anionic membrane surface effectively neutralizes its charge, leading to the reorientation of water mols. close to the lipid/water interface and to the partial release of counterions to the water phase. In certain cases one has even an overcharging of the membrane, which was shown to be a cooperative effect of polymer charges and lipid counterions. Protonated amine groups of polycations are found to interact preferably with head groups of anionic lipids, giving rise to formation of hydrogen bonds and to a noticeable lateral immobilization of the lipids. While all the above findings are mostly defined by the overall charge of a polymer, we found that the polymer architecture also matters. In particular, PVA and PEI are able to accumulate anionic PG lipids on the membrane surface, leading to lipid segregation. In turn, PLL whose charge twice exceeds charges of PVA/PEI does not induce such lipid segregation due to its considerably less compact architecture and relatively long side chains. We also show that partitioning of a polycation into the lipid/water interface is an interplay between its protonation level (the overall charge) and hydrophobicity of the backbone. Therefore, a possible strategy in creating highly efficient antimicrobial polymeric agents could be in tuning these polycation's properties through proper combination of protonated and hydrophobic blocks.
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    Recently, two groups of rhodopsin genes were identified in large double-stranded DNA viruses. The structure and function of viral rhodopsins are unknown. We present functional characterization and high-resolution structure of an Organic Lake Phycodnavirus rhodopsin II (OLPVRII) of group 2. It forms a pentamer, with a symmetrical, bottle-like central channel with the narrow vestibule in the cytoplasmic part covered by a ring of 5 arginines, whereas 5 phenylalanines form a hydrophobic barrier in its exit. The proton donor E42 is placed in the helix B. The structure is unique among the known rhodopsins. Structural and functional data and molecular dynamics suggest that OLPVRII might be a light-gated pentameric ion channel analogous to pentameric ligand-gated ion channels, however, future patch clamp experiments should prove this directly. The data shed light on a fundamentally distinct branch of rhodopsins and may contribute to the understanding of virus-host interactions in ecologically important marine protists.
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  • Abstract

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    Figure 1

    Figure 1. Water-based scheme to calculate the electrostatic potential. First, the long-range part of the potential is calculated by solving the Poisson equation on the grid using the SPME method. Second, each water molecule is assigned a potential averaged over a sphere around its center of geometry, resulting in a distribution of water-molecule potentials. Third, the frame is fitted onto the reference structure and the grid of the final electrostatic-potential map is built around the biomolecule. Fourth, the water-molecule potentials are distributed over the nodes of the electrostatic-potential map, followed by normalization of the node potential based on the number of contributing water molecules. The final map is used for the quantitative analysis of electrostatics, e.g., to generate a potential profile.

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    Figure 2

    Figure 2. Calculation of the electrostatic potential within the pore of the P2X3 cation channel. (a) (Left) Structure of the P2X3 receptor transmembrane domain without the ATP-binding ectodomain and embedded in a lipid membrane. The oxygen and hydrogen atoms of water molecules and the phosphorus atoms around the protein are shown as red, white, and orange spheres, respectively. (Middle) The water-occupancy map, contoured at an occupancy level of 0.1. (Right) Electrostatic-potential map, obtained with β = 20 nm–1 and contoured at −400 mV. The maps were calculated from the first 100 ns block of the 1 μs trajectory. (b) Electrostatic-potential profiles along the P2X3 pore, calculated from the first 100 ns block of the 1 μs trajectory using different values for the β parameter. (c) Average electrostatic-potential profile along the P2X3 pore based on the whole 1 μs trajectory (β = 20 nm–1). Whiskers indicate the standard deviation of the potential, as calculated for 10 separate 100 ns blocks.

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    Figure 3

    Figure 3. Electrostatic-potential profiles along the proteolipidic pore of TMEM16 lipid scramblases. (a) Dimeric structure of nhTMEM16 in a lipid membrane. Protomers are colored white and gray; phosphorus atoms are shown in orange. (b,c) Side views of nhTMEM16 in the mixed POPC:POPS membrane (b) and of TMEM16K in the POPC membrane (c), together with the examples of the masked water-occupancy maps used to calculate the electrostatic-potential profiles. The maps were contoured at an occupancy level of 0.1. Phosphorus atoms of POPC and POPS are shown in orange and cyan, respectively. (d) Average electrostatic-potential profiles along the proteolipidic pore of TMEM16K and nhTMEM16 in pure POPC and mixed POPC:POPS membranes. The profiles were averaged over 1 μs trajectories. Whiskers indicate the standard deviation of the potential, as calculated for 10 separate 100 ns blocks.

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    Figure 4

    Figure 4. Sodium binding increases the electrostatic potential at the aspartate-binding site of GltPh. (a) Structure of the aspartate-bound GltPh protomer in the outward-facing conformation shown together with different occupancy states of the binding sites. The aspartate molecule is shown in violet, and Na+ ions are shown as blue spheres. The violet cross in the apo panel indicates the position where the potential was measured. Membrane borders are shown schematically. (b) Time courses of electrostatic potential in the aspartate-binding site (violet) and Na+ occupancy of the Na1 site (blue) in one of the protomers upon spontaneous Na+ binding in an MD simulation initiated from the apo state. The time courses are shown as running averages with 50 ns windows. (c) Electrostatic potential in the aspartate-binding site in different states. Each data point is an average potential from a 50 ns block of a single protomer trajectory, whiskers indicate the 5th and 95th percentiles, and a median value is shown for each state.

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    Figure 5

    Figure 5. Local effects of polycations on DNA electrostatics. (a) Structure of DNA in complex with cationic polymers PVA (left) and PAA (right). The backbone and grooves of DNA are shown in red and white, respectively. Polymers are shown as spheres with nitrogen atoms in blue and carbon atoms in teal (PVA) and yellow (PAA); hydrogen atoms are omitted. (b) Radial distribution of electrostatic potential around the central axis of DNA either in free form or in complex with PVA or PAA, calculated either globally (top), or separately for major (middle) and minor (bottom) grooves. Whiskers indicate the standard deviation of the potential, calculated separately for 100 ns blocks.

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      Li, Chuan; Jia, Zhe; Chakravorty, Arghya; Pahari, Swagata; Peng, Yunhui; Basu, Sankar; Koirala, Mahesh; Panday, Shailesh Kumar; Petukh, Marharyta; Li, Lin; Alexov, Emil
      Journal of Computational Chemistry (2019), 40 (28), 2502-2508CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      Electrostatic potential, energies, and forces affect virtually any process in mol. biol., however, computing these quantities is a difficult task due to irregularly shaped macromols. and the presence of water. Here, the authors report a new edition of the popular software package DelPhi along with describing its functionalities. The new DelPhi is a C++ object-oriented package supporting various levels of multiprocessing and memory distribution. It is demonstrated that multiprocessing results in significant improvement of computational time. Furthermore, for computations requiring large grid size (large macromol. assemblages), the approach of memory distribution is shown to reduce the requirement of RAM and thus permitting large-scale modeling to be done on Linux clusters with moderate architecture. The new release comes with new features, whose functionalities and applications are described as well.
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    3. 3
      Baker, N. A.; Sept, D.; Joseph, S.; Holst, M. J.; McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10037– 10041,  DOI: 10.1073/pnas.181342398
      3
      Electrostatics of nanosystems: application to microtubules and the ribosome
      Baker, Nathan A.; Sept, David; Joseph, Simpson; Holst, Michael J.; McCammon, J. Andrew
      Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (18), 10037-10041CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Evaluation of the electrostatic properties of biomols. has become a std. practice in mol. biophysics. Foremost among the models used to elucidate the electrostatic potential is the Poisson-Boltzmann equation; however, existing methods for solving this equation have limited the scope of accurate electrostatic calcns. to relatively small biomol. systems. Here we present the application of numerical methods to enable the trivially parallel soln. of the Poisson-Boltzmann equation for supramol. structures that are orders of magnitude larger in size. As a demonstration of this methodol., electrostatic potentials have been calcd. for large microtubule and ribosome structures. The results point to the likely role of electrostatics in a variety of activities of these structures.
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    4. 4
      Callenberg, K. M.; Choudhary, O. P.; de Forest, G. L.; Gohara, D. W.; Baker, N. A.; Grabe, M. APBSmem: a graphical interface for electrostatic calculations at the membrane. PLoS One 2010, 5, e12722  DOI: 10.1371/journal.pone.0012722
      There is no corresponding record for this reference.
    5. 5
      Dong, F.; Olsen, B.; Baker, N. A. Computational methods for biomolecular electrostatics. Methods Cell Biol. 2008, 84, 843– 870
      5
      Computational methods for biomolecular electrostatics
      Dong, Feng; Olsen, Brett; Baker, Nathan A.
      Methods in Cell Biology (2008), 84 (Biophysical Tools for Biologists, Volume One), 843-870CODEN: MCBLAG; ISSN:0091-679X. (Elsevier)
      A review. An understanding of intermol. interactions is essential for insight into how cells develop, operate, communicate, and control their activities. Such interactions include several components: contributions from linear, angular, and torsional forces in covalent bonds, van der waals forces, as well as electrostatics. Among the various components of mol. interactions, electrostatics are of special importance because of their long range and their influence on polar or charged mols., including water, aq. ions, and amino or nucleic acids, which are some of the primary components of living systems. Electrostatics, therefore, play important roles in detg. the structure, motion, and function of a wide range of biol. mols. This chapter presents a brief overview of electrostatic interactions in cellular systems, with a particular focus on how computational tools can be used to investigate these types of interactions.
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    6. 6
      Wang, L. Measurements and implications of the membrane dipole potential. Annu. Rev. Biochem. 2012, 81, 615– 635,  DOI: 10.1146/annurev-biochem-070110-123033
      6
      Measurements and implications of the membrane dipole potential
      Wang, Liguo
      Annual Review of Biochemistry (2012), 81 (), 615-635CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)
      A review. There are three kinds of membrane potentials: the surface potentials, resulting from the accumulation of charges at the membrane surfaces; the transmembrane potential, detd. by imbalance of charge in the aq. solns.; and the dipole potential, a membrane-internal potential from the dipolar components of the phospholipids and interface water. The abs. value of the dipole potential has been very difficult to measure, although its value has been estd. to be at 200-1000 mV from ion translocation rates (detd. by the planar lipid bilayer method), the surface potential of lipid monolayers (detd. by the lipid monolayer method), mol.-dynamics calcns., and electron scattering using cryoelectron microscopy (cryo-EM). Spectroscopy methods have also been used to monitor the dipole potential changes on the basis of the obsd. fluorescence changes of voltage-sensitive probes. The dipole potential accounts for the much larger permeability of a bare phospholipid membrane to anions than cations and affects the conformation and function of membrane proteins.
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    7. 7
      Warshel, A.; Sharma, P. K.; Kato, M.; Parson, W. W. Modeling electrostatic effects in proteins. Biochim. Biophys. Acta, Proteins Proteomics 2006, 1764, 1647– 1676,  DOI: 10.1016/j.bbapap.2006.08.007
      7
      Modeling electrostatic effects in proteins
      Warshel, Arieh; Sharma, Pankaz K.; Kato, Mitsunori; Parson, William W.
      Biochimica et Biophysica Acta, Proteins and Proteomics (2006), 1764 (11), 1647-1676CODEN: BBAPBW; ISSN:1570-9639. (Elsevier Ltd.)
      A review. Electrostatic energies provide what is perhaps the most effective tool for structure-function correlation of biol. mols. This review considers the current state of simulations of electrostatic energies in macromols. as well as the early developments of this field. We focus on the relationship between microscopic and macroscopic models, considering the convergence problems of the microscopic models and the fact that the dielec. consts. in semimacroscopic models depend on the definition and the specific treatment. The advances and the challenges in the field are illustrated considering a wide range of functional properties including pKa's, redox potentials, ion and proton channels, enzyme catalysis, ligand binding and protein stability. We conclude by pointing out that, despite the current problems and the significant misunderstandings in the field, there is an overall progress that should lead eventually to quant. descriptions of electrostatic effects in proteins and thus to quant. descriptions of the function of proteins.
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    8. 8
      Cisneros, G. A.; Karttunen, M.; Ren, P.; Sagui, C. Classical electrostatics for biomolecular simulations. Chem. Rev. 2014, 114, 779– 814,  DOI: 10.1021/cr300461d
      8
      Classical Electrostatics for Biomolecular Simulations
      Cisneros, G. Andres; Karttunen, Mikko; Ren, Pengyu; Sagui, Celeste
      Chemical Reviews (Washington, DC, United States) (2014), 114 (1), 779-814CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      In this review, the authors primarily treat electrostatic methods for classical biomol. simulations in explicit solvent, with special emphasis on the accuracy of the electrostatic representation. The first part of the article is dedicated to reviewing computational methods for dealing with the long-range nature of the electrostatic interactions, including traditional methods as well as recent extensions and developments. The second part of the article is dedicated to reviewing current methods for representing the mol. electronic charge cloud, that go well beyond the point-charge representation. In addn., the authors discuss various multiscale approaches at the quantum mechanics/mol. mechanics level and at the mol. mechanics/coarse-grain level. The general trends in both cases are toward more accuracy and proper treatment of electrostatics. The authors finish the article by describing other challenging developments and giving the perspective on the current state of the field.
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    9. 9
      Hollingsworth, S. A.; Dror, R. O. Molecular Dynamics Simulation for All. Neuron 2018, 99, 1129– 1143,  DOI: 10.1016/j.neuron.2018.08.011
      9
      Molecular Dynamics Simulation for All
      Hollingsworth, Scott A.; Dror, Ron O.
      Neuron (2018), 99 (6), 1129-1143CODEN: NERNET; ISSN:0896-6273. (Cell Press)
      A review. The impact of mol. dynamics (MD) simulations in mol. biol. and drug discovery has expanded dramatically in recent years. These simulations capture the behavior of proteins and other biomols. in full at. detail and at very fine temporal resoln. Major improvements in simulation speed, accuracy, and accessibility, together with the proliferation of exptl. structural data, have increased the appeal of biomol. simulation to experimentalists-a trend particularly noticeable in, although certainly not limited to, neuroscience. Simulations have proven valuable in deciphering functional mechanisms of proteins and other biomols., in uncovering the structural basis for disease, and in the design and optimization of small mols., peptides, and proteins. Here we describe, in practical terms, the types of information MD simulations can provide and the ways in which they typically motivate further exptl. work.
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    10. 10
      Kutzner, C.; Köpfer, D. A.; Machtens, J.-P.; de Groot, B. L.; Song, C.; Zachariae, U. Insights into the function of ion channels by computational electrophysiology simulations. Biochim. Biophys. Acta, Biomembr. 2016, 1858, 1741– 1752,  DOI: 10.1016/j.bbamem.2016.02.006
      10
      Insights into the function of ion channels by computational electrophysiology simulations
      Kutzner, Carsten; Koepfer, David A.; Machtens, Jan-Philipp; de Groot, Bert L.; Song, Chen; Zachariae, Ulrich
      Biochimica et Biophysica Acta, Biomembranes (2016), 1858 (7_Part_B), 1741-1752CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
      A review. Ion channels are of universal importance for all cell types and play key roles in cellular physiol. and pathol. Increased insight into their functional mechanisms is crucial to enable drug design on this important class of membrane proteins, and to enhance our understanding of some of the fundamental features of cells. This review presents the concepts behind the recently developed simulation protocol Computational Electrophysiol. (CompEL), which facilitates the atomistic simulation of ion channels in action. In addn., the review provides guidelines for its application in conjunction with the mol. dynamics software package GROMACS. We first lay out the rationale for designing CompEL as a method that models the driving force for ion permeation through channels the way it is established in cells, i.e., by electrochem. ion gradients across the membrane. This is followed by an outline of its implementation and a description of key settings and parameters helpful to users wishing to set up and conduct such simulations. In recent years, key mechanistic and biophys. insights have been obtained by employing the CompEL protocol to address a wide range of questions on ion channels and permeation. We summarize these recent findings on membrane proteins, which span a spectrum from highly ion-selective, narrow channels to wide diffusion pores. Finally we discuss the future potential of CompEL in light of its limitations and strengths. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.
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    11. 11
      Lin, Y.-L.; Aleksandrov, A.; Simonson, T.; Roux, B. An Overview of Electrostatic Free Energy Computations for Solutions and Proteins. J. Chem. Theory Comput. 2014, 10, 2690– 2709,  DOI: 10.1021/ct500195p
      11
      An Overview of Electrostatic Free Energy Computations for Solutions and Proteins
      Lin, Yen-Lin; Aleksandrov, Alexey; Simonson, Thomas; Roux, Benoit
      Journal of Chemical Theory and Computation (2014), 10 (7), 2690-2709CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      A review. Free energy simulations for electrostatic and charging processes in complex mol. systems encounter specific difficulties owing to the long-range, 1/r Coulomb interaction. To calc. the solvation free energy of a simple ion, it is essential to take into account the polarization of nearby solvent but also the electrostatic potential drop across the liq.-gas boundary, however distant. The latter does not exist in a simulation model based on periodic boundary conditions because there is no phys. boundary to the system. An important consequence is that the ref. value of the electrostatic potential is not an ion in a vacuum. Also, in an infinite system, the electrostatic potential felt by a perturbing charge is conditionally convergent and dependent on the choice of computational conventions. Furthermore, with Ewald lattice summation and tinfoil conducting boundary conditions, the charges experience a spurious shift in the potential that depends on the details of the simulation system such as the vol. fraction occupied by the solvent. All these issues can be handled with established computational protocols, as reviewed here and illustrated for several small ions and three solvated proteins.
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    12. 12
      Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, 10089– 10092,  DOI: 10.1063/1.464397
      12
      Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems
      Darden, Tom; York, Darrin; Pedersen, Lee
      Journal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.
      An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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    13. 13
      Essmann, U.; Perera, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577– 8593,  DOI: 10.1063/1.470117
      13
      A smooth particle mesh Ewald method
      Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.; Darden, Tom; Lee, Hsing; Pedersen, Lee G.
      Journal of Chemical Physics (1995), 103 (19), 8577-93CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      The previously developed particle mesh Ewald method is reformulated in terms of efficient B-spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p ≥ 1. Furthermore, efficient calcn. of the virial tensor follows. Use of B-splines in the place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. The authors demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomol. systems with many thousands of atoms and this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 Å or less.
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    14. 14
      Aksimentiev, A.; Schulten, K. Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map. Biophys. J. 2005, 88, 3745– 3761,  DOI: 10.1529/biophysj.104.058727
      14
      Imaging α-hemolysin with molecular dynamics: Ionic conductance, osmotic permeability, and the electrostatic potential map
      Aksimentiev, Aleksij; Schulten, Klaus
      Biophysical Journal (2005), 88 (6), 3745-3761CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
      α-Hemolysin of Staphylococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, α-hemolysin is the principal component in several biotechnol. applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technol. for DNA sequencing. Through large-scale mol. dynamics simulations, we studied the permeability of the α-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of ∼300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water soln. of KCl. Monitoring the fluctuations of the pore structure revealed an asym., on av., cross section of the α-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of α-hemolysin and a set of electrostatic potential maps. The selectivity of α-hemolysin to Cl- was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quant. agreement with available exptl. data. Analyzing trajectories of all water mol., we computed the α-hemolysin's osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk soln.; the protonation of these residues was obsd. to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the α-hemolysin channel.
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    15. 15
      Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graphics 1996, 14, 33– 38,  DOI: 10.1016/0263-7855(96)00018-5
      15
      VDM: visual molecular dynamics
      Humphrey, William; Dalke, Andrew; Schulten, Klaus
      Journal of Molecular Graphics (1996), 14 (1), 33-8, plates, 27-28CODEN: JMGRDV; ISSN:0263-7855. (Elsevier)
      VMD is a mol. graphics program designed for the display and anal. of mol. assemblies, in particular, biopolymers such as proteins and nucleic acids. VMD can simultaneously display any no. of structures using a wide variety of rendering styles and coloring methods. Mols. are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resoln. raster images of displayed mols. may be produced by generating input scripts for use by a no. of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate mol. dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biol., which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs, VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
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    16. 16
      Enkavi, G.; Tajkhorshid, E. Simulation of spontaneous substrate binding revealing the binding pathway and mechanism and initial conformational response of GlpT. Biochemistry 2010, 49, 1105– 1114,  DOI: 10.1021/bi901412a
      16
      Simulation of Spontaneous Substrate Binding Revealing the Binding Pathway and Mechanism and Initial Conformational Response of GlpT
      Enkavi, Giray; Tajkhorshid, Emad
      Biochemistry (2010), 49 (6), 1105-1114CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      Glycerol 3-phosphate transporter (GlpT) mediates the import of glycerol 3-phosphate (G3P) using the gradient of inorg. phosphate (Pi). To study the process and mechanism of substrate binding and to investigate the protein's initial response, we performed equil. simulations of wild-type GlpT and several of its mutant forms in membranes in the presence of all physiol. relevant substrates (Pi-, Pi2-, G3P-, and G3P2-). The simulations capture spontaneous substrate binding of GlpT, driven by the pos. electrostatic potential of the lumen. K80 is found to act as a "hook" making the first encounter with the substrate and guiding it toward the binding site, where it binds tightly to R45, a key binding site residue that acts as a "fork" holding the substrate. R269 establishes no direct contact with the substrate during the simulations, a surprising behavior given its structural pseudosymmetry to R45. In all substrate-bound systems, partial closing of the cytoplasmic half of GlpT was obsd. The substrate appears to stabilize the partially occluded state, as in the two apo simulations either no closing was obsd. or the protein reverted to its open form toward the end of the simulation, whereas in all substrate-bound systems, a stable partially closed state was produced. Along with the modulation of the periplasmic salt bridge network, these substrate-induced events destabilize the periplasmic half while inducing a closure in the cytoplasmic half, thus capturing the early stages of the proposed rocker-switch mechanism in GlpT.
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    17. 17
      Arcario, M. J.; Tajkhorshid, E. Membrane-induced structural rearrangement and identification of a novel membrane anchor in talin F2F3. Biophys. J. 2014, 107, 2059– 2069,  DOI: 10.1016/j.bpj.2014.09.022
      17
      Membrane-Induced Structural Rearrangement and Identification of a Novel Membrane Anchor in Talin F2F3
      Arcario, Mark J.; Tajkhorshid, Emad
      Biophysical Journal (2014), 107 (9), 2059-2069CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      Exptl. challenges assocd. with characterization of the membrane-bound form of talin have prevented us from understanding the mol. mechanism of its membrane-dependent integrin activation. Here, utilizing what we believe to be a novel membrane mimetic model, we present a reproducible model of membrane-bound talin obsd. across multiple independent simulations. We characterize both local and global membrane-induced structural transitions that successfully reconcile discrepancies between biochem. and structural studies and provide insight into how talin might modulate integrin function. Membrane binding of talin, captured in unbiased simulations, proceeds through three distinct steps: initial electrostatic recruitment of the F2 subdomain to anionic lipids via several basic residues; insertion of an initially buried, conserved hydrophobic anchor into the membrane; and assocn. of the F3 subdomain with the membrane surface through a large, interdomain conformational change. These latter two steps, to our knowledge, have not been obsd. or described previously. Electrostatic anal. shows talin F2F3 to be highly polarized, with a highly pos. underside, which we attribute to the initial electrostatic recruitment, and a neg. top face, which can help orient the protein optimally with respect to the membrane, thereby reducing the no. of unproductive membrane collision events.
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    18. 18
      Frigo, M.; Johnson, S. G. The Design and Implementation of FFTW3. Proc. IEEE 2005, 93, 216– 231,  DOI: 10.1109/JPROC.2004.840301
      There is no corresponding record for this reference.
    19. 19
      Phillips, J. C.; Hardy, D. J.; Maia, J. D. C.; Stone, J. E.; Ribeiro, J. V.; Bernardi, R. C.; Buch, R.; Fiorin, G.; Hénin, J.; Jiang, W.; McGreevy, R.; Melo, M. C. R.; Radak, B. K.; Skeel, R. D.; Singharoy, A.; Wang, Y.; Roux, B.; Aksimentiev, A.; Luthey-Schulten, Z.; Kalé, L. V.; Schulten, K.; Chipot, C.; Tajkhorshid, E. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J. Chem. Phys. 2020, 153, 044130  DOI: 10.1063/5.0014475
      19
      Scalable molecular dynamics on CPU and GPU architectures with NAMD
      Phillips, James C.; Hardy, David J.; Maia, Julio D. C.; Stone, John E.; Ribeiro, Joao V.; Bernardi, Rafael C.; Buch, Ronak; Fiorin, Giacomo; Henin, Jerome; Jiang, Wei; McGreevy, Ryan; Melo, Marcelo C. R.; Radak, Brian K.; Skeel, Robert D.; Singharoy, Abhishek; Wang, Yi; Roux, Benoit; Aksimentiev, Aleksei; Luthey-Schulten, Zaida; Kale, Laxmikant V.; Schulten, Klaus; Chipot, Christophe; Tajkhorshid, Emad
      Journal of Chemical Physics (2020), 153 (4), 044130CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      A review. NAMD is a mol. dynamics program designed for high-performance simulations of very large biol. objects on CPU- and GPU-based architectures. NAMD offers scalable performance on petascale parallel supercomputers consisting of hundreds of thousands of cores, as well as on inexpensive commodity clusters commonly found in academic environments. It is written in C++ and leans on Charm++ parallel objects for optimal performance on low-latency architectures. NAMD is a versatile, multipurpose code that gathers state-of-the-art algorithms to carry out simulations in apt thermodn. ensembles, using the widely popular CHARMM, AMBER, OPLS, and GROMOS biomol. force fields. Here, the authors review the main features of NAMD that allow both equil. and enhanced-sampling mol. dynamics simulations with numerical efficiency. The authors describe the underlying concepts used by NAMD and their implementation, most notably for handling long-range electrostatics; controlling the temp., pressure, and pH; applying external potentials on tailored grids; leveraging massively parallel resources in multiple-copy simulations; and hybrid quantum-mech./mol.-mech. descriptions. The authors detail the variety of options offered by NAMD for enhanced-sampling simulations aimed at detg. free-energy differences of either alchem. or geometrical transformations and outline their applicability to specific problems. Last, the roadmap for the development of NAMD and the authors' current efforts toward achieving optimal performance on GPU-based architectures, for pushing back the limitations that have prevented biol. realistic billion-atom objects to be fruitfully simulated, and for making large-scale simulations less expensive and easier to set up, run, and analyze are discussed. NAMD is distributed free of charge with its source code at www.ks.uiuc.edu. (c) 2020 American Institute of Physics.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFajsL3J&md5=aa6378c15e48addc4b6b02523e55427f
    20. 20
      Mansoor, S. E.; Lü, W.; Oosterheert, W.; Shekhar, M.; Tajkhorshid, E.; Gouaux, E. X-ray structures define human P2X(3) receptor gating cycle and antagonist action. Nature 2016, 538, 66– 71,  DOI: 10.1038/nature19367
      20
      X-ray structures define human P2X3 receptor gating cycle and antagonist action
      Mansoor, Steven E.; Lu, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric
      Nature (London, United Kingdom) (2016), 538 (7623), 66-71CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiol. and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacol. agents.
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    21. 21
      Wolf, M. G.; Hoefling, M.; Aponte-Santamaría, C.; Grubmüller, H.; Groenhof, G. g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation. J. Comput. Chem. 2010, 31, 2169– 2174,  DOI: 10.1002/jcc.21507
      21
      g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation
      Wolf, Maarten G.; Hoefling, Martin; Aponte-Santamaria, Camilo; Grubmueller, Helmut; Groenhof, Gerrit
      Journal of Computational Chemistry (2010), 31 (11), 2169-2174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      To efficiently insert a protein into an equilibrated and fully hydrated membrane with minimal membrane perturbation the authors present a computational tool, called g_membed, which is part of the Gromacs suite of programs. The input consists of an equilibrated membrane system, either flat or curved, and a protein structure in the right position and orientation with respect to the lipid bilayer. G_membed first decreases the width of the protein in the xy-plane and removes all mols. (generally lipids and waters) that overlap with the narrowed protein. Then the protein is grown back to its full size in a short mol. dynamics simulation (typically 1000 steps), thereby pushing the lipids away to optimally accommodate the protein in the membrane. After embedding the protein in the membrane, both the lipid properties and the hydration layer are still close to equil. Thus, only a short equilibration run (less then 1 ns in the cases tested) is required to re-equilibrate the membrane. Its simplicity makes g_membed very practical for use in scripting and high-throughput mol. dynamics simulations. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.
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    22. 22
      Abraham, M. J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J. C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015, 1–2, 19– 25,  DOI: 10.1016/j.softx.2015.06.001
      There is no corresponding record for this reference.
    23. 23
      Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 1984, 81, 3684– 3690,  DOI: 10.1063/1.448118
      23
      Molecular dynamics with coupling to an external bath
      Berendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R.
      Journal of Chemical Physics (1984), 81 (8), 3684-90CODEN: JCPSA6; ISSN:0021-9606.
      In mol. dynamics (MD) simulations, the need often arises to maintain such parameters as temp. or pressure rather than energy and vol., or to impose gradients for studying transport properties in nonequil. MD. A method is described to realize coupling to an external bath with const. temp. or pressure with adjustable time consts. for the coupling. The method is easily extendable to other variables and to gradients, and can be applied also to polyat. mols. involving internal constraints. The influence of coupling time consts. on dynamical variables is evaluated. A leap-frog algorithm is presented for the general case involving constraints with coupling to both a const. temp. and a const. pressure bath.
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    24. 24
      Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007, 126, 014101  DOI: 10.1063/1.2408420
      24
      Canonical sampling through velocity rescaling
      Bussi, Giovanni; Donadio, Davide; Parrinello, Michele
      Journal of Chemical Physics (2007), 126 (1), 014101/1-014101/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      The authors present a new mol. dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains const. during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. The authors illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liq. phases. Its performance is excellent and largely independent of the thermostat parameter also with regard to the dynamic properties.
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    25. 25
      Huang, J.; Rauscher, S.; Nawrocki, G.; Ran, T.; Feig, M.; de Groot, B. L.; Grubmüller, H.; MacKerell, A. D. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 2017, 14, 71– 73,  DOI: 10.1038/nmeth.4067
      25
      CHARMM36m: an improved force field for folded and intrinsically disordered proteins
      Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz; Ran, Ting; Feig, Michael; de Groot, Bert L.; Grubmuller, Helmut; MacKerell, Alexander D. Jr
      Nature Methods (2017), 14 (1), 71-73CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      The all-atom additive CHARMM36 protein force field is widely used in mol. modeling and simulations. We present its refinement, CHARMM36m (http://mackerell.umaryland.edu/charmm_ff.shtml), with improved accuracy in generating polypeptide backbone conformational ensembles for intrinsically disordered peptides and proteins.
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    26. 26
      Klauda, J. B.; Venable, R. M.; Freites, J. A.; O’Connor, J. W.; Tobias, D. J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A. D.; Pastor, R. W. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 2010, 114, 7830– 7843,  DOI: 10.1021/jp101759q
      26
      Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
      Klauda, Jeffery B.; Venable, Richard M.; Freites, J. Alfredo; O'Connor, Joseph W.; Tobias, Douglas J.; Mondragon-Ramirez, Carlos; Vorobyov, Igor; MacKerell, Alexander D., Jr.; Pastor, Richard W.
      Journal of Physical Chemistry B (2010), 114 (23), 7830-7843CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      A significant modification to the additive all-atom CHARMM lipid force field (FF) is developed and applied to phospholipid bilayers with both choline and ethanolamine contg. head groups and with both satd. and unsatd. aliph. chains. Motivated by the current CHARMM lipid FF (C27 and C27r) systematically yielding values of the surface area per lipid that are smaller than exptl. ests. and gel-like structures of bilayers well above the gel transition temp., selected torsional, Lennard-Jones and partial at. charge parameters were modified by targeting both quantum mech. (QM) and exptl. data. QM calcns. ranging from high-level ab initio calcns. on small mols. to semiempirical QM studies on a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer in combination with exptl. thermodn. data were used as target data for parameter optimization. These changes were tested with simulations of pure bilayers at high hydration of the following six lipids: DPPC, 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-phosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2-dioleoyl-sn-phosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-phosphatidylethanolamine (POPE); simulations of a low hydration DOPC bilayer were also performed. Agreement with exptl. surface area is on av. within 2%, and the d. profiles agree well with neutron and x-ray diffraction expts. NMR deuterium order parameters (SCD) are well predicted with the new FF, including proper splitting of the SCD for the aliph. carbon adjacent to the carbonyl for DPPC, POPE, and POPC bilayers. The area compressibility modulus and frequency dependence of 13C NMR relaxation rates of DPPC and the water distribution of low hydration DOPC bilayers also agree well with expt. Accordingly, the presented lipid FF, referred to as C36, allows for mol. dynamics simulations to be run in the tensionless ensemble (NPT), and is anticipated to be of utility for simulations of pure lipid systems as well as heterogeneous systems including membrane proteins.
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    27. 27
      Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983, 79, 926– 935,  DOI: 10.1063/1.445869
      27
      Comparison of simple potential functions for simulating liquid water
      Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.
      Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.
      Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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    28. 28
      Brunner, J. D.; Lim, N. K.; Schenck, S.; Duerst, A.; Dutzler, R. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature 2014, 516, 207– 212,  DOI: 10.1038/nature13984
      28
      X-ray structure of a calcium-activated TMEM16 lipid scramblase
      Brunner, Janine D.; Lim, Novandy K.; Schenck, Stephan; Duerst, Alessia; Dutzler, Raimund
      Nature (London, United Kingdom) (2014), 516 (7530), 207-212CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca2+-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria hematococca that operates as a Ca2+-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helixes and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbors a conserved Ca2+-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca2+ coordination affect both lipid scrambling in N. hematococca TMEM16 and ion conduction in the Cl- channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca2+ activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.
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    29. 29
      Bushell, S. R.; Pike, A. C.; Falzone, M. E.; Rorsman, N. J.; Ta, C. M.; Corey, R. A.; Newport, T. D.; Christianson, J. C.; Scofano, L. F.; Shintre, C. A.; Tessitore, A.; Chu, A.; Wang, Q.; Shrestha, L.; Mukhopadhyay, S. M. M.; Love, J. D.; Burgess-Brown, N. A.; Sitsapesan, R.; Stansfeld, P. J.; Huiskonen, J. T.; Tammaro, P.; Accardi, A.; Carpenter, E. P. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nat. Commun. 2019, 10, 3956  DOI: 10.1038/s41467-019-11753-1
      29
      The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
      Bushell Simon R; Pike Ashley C W; Shintre Chitra A; Tessitore Annamaria; Chu Amy; Wang Qinrui; Shrestha Leela; Mukhopadhyay Shubhashish M M; Burgess-Brown Nicola A; Carpenter Elisabeth P; Falzone Maria E; Accardi Alessio; Rorsman Nils J G; Ta Chau M; Scofano Lara F; Sitsapesan Rebecca; Tammaro Paolo; Rorsman Nils J G; Ta Chau M; Corey Robin A; Newport Thomas D; Wang Qinrui; Stansfeld Phillip J; Newport Thomas D; Christianson John C; Shintre Chitra A; Tessitore Annamaria; Chu Amy; Love James D; Love James D; Huiskonen Juha T; Accardi Alessio; Accardi Alessio
      Nature communications (2019), 10 (1), 3956 ISSN:.
      Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.
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    30. 30
      Kostritskii, A. Y.; Machtens, J.-P. Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases. Nat. Commun. 2021, in press, DOI: 10.1038/s41467-021-22724-w .
      There is no corresponding record for this reference.
    31. 31
      Alleva, C.; Kovalev, K.; Astashkin, R.; Berndt, M. I.; Baeken, C.; Balandin, T.; Gordeliy, V.; Fahlke, C.; Machtens, J.-P. Na+-dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters. Sci. Adv. 2020, 6, eaba9854  DOI: 10.1126/sciadv.aba9854
      There is no corresponding record for this reference.
    32. 32
      Lomize, M. A.; Pogozheva, I. D.; Joo, H.; Mosberg, H. I.; Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 2012, 40, D370– D376,  DOI: 10.1093/nar/gkr703
      32
      OPM database and PPM web server: resources for positioning of proteins in membranes
      Lomize, Mikhail A.; Pogozheva, Irina D.; Joo, Hyeon; Mosberg, Henry I.; Lomize, Andrei L.
      Nucleic Acids Research (2012), 40 (D1), D370-D376CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The Orientations of Proteins in Membranes (OPM) database is a curated web resource that provides spatial positions of membrane-bound peptides and proteins of known three-dimensional structure in the lipid bilayer, together with their structural classification, topol. and intracellular localization. OPM currently contains more than 1200 transmembrane and peripheral proteins and peptides from approx. 350 organisms that represent approx. 3800 Protein Data Bank entries. Proteins are classified into classes, superfamilies and families and assigned to 21 distinct membrane types. Spatial positions of proteins with respect to the lipid bilayer are optimized by the PPM 2.0 method that accounts for the hydrophobic, hydrogen bonding and electrostatic interactions of the proteins with the anisotropic water-lipid environment described by the dielec. const. and hydrogen-bonding profiles. The OPM database is freely accessible at http://opm.phar.umich.edu. Data can be sorted, searched or retrieved using the hierarchical classification, source organism, localization in different types of membranes. The database offers downloadable coordinates of proteins and peptides with membrane boundaries. A gallery of protein images and several visualization tools are provided. The database is supplemented by the PPM server (http://opm.phar.umich.edu/server.php) which can be used for calcg. spatial positions in membranes of newly detd. proteins structures or theor. models.
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    33. 33
      Lindorff-Larsen, K.; Piana, S.; Palmo, K.; Maragakis, P.; Klepeis, J. L.; Dror, R. O.; Shaw, D. E. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins: Struct., Funct., Bioinf. 2010, 78, 1950– 1958,  DOI: 10.1002/prot.22711
      33
      Improved side-chain torsion potentials for the Amber ff99SB protein force field
      Lindorff-Larsen, Kresten; Piana, Stefano; Palmo, Kim; Maragakis, Paul; Klepeis, John L.; Dror, Ron O.; Shaw, David E.
      Proteins: Structure, Function, and Bioinformatics (2010), 78 (8), 1950-1958CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)
      Recent advances in hardware and software have enabled increasingly long mol. dynamics (MD) simulations of biomols., exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, the authors further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, the authors used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, the authors optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mech. calcns. Finally, the authors used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of exptl. NMR measurements that directly probe side-chain conformations. The new force field, which the authors have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc.
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    34. 34
      Berger, O.; Edholm, O.; Jähnig, F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys. J. 1997, 72, 2002– 2013,  DOI: 10.1016/S0006-3495(97)78845-3
      34
      Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature
      Berger, Oliver; Edholm, Olle; Jahnig, Fritz
      Biophysical Journal (1997), 72 (5), 2002-2013CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
      Mol. dynamics simulations of 500 ps were performed on a system consisting of a bilayer of 64 mols. of the lipid dipalmitoylphosphatidylcholine and 23 water mols. per lipid at an isotropic pressure of 1 atm and 50°. Special attention was devoted to reproduce the correct d. of the lipid, because this quantity is known exptl. with a precision better than 1%. For this purpose, the Lennard-Jones parameters of the hydrocarbon chains were adjusted by simulating a system consisting of 128 pentadecane mols. and varying the Lennard-Jones parameters until the exptl. d. and heat of vaporization were obtained. With these parameters the lipid d. resulted in perfect agreement with the exptl. d. The orientational order parameter of the hydrocarbon chains agreed perfectly well with the exptl. values, which, because of its correlation with the area per lipid, makes it possible to give a proper est. of the area per lipid of 0.61±0.1 nm2.
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    35. 35
      Joung, I. S.; Cheatham, T. E. Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations. J. Phys. Chem. B 2008, 112, 9020– 9041,  DOI: 10.1021/jp8001614
      35
      Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations
      Joung, In Suk; Cheatham, Thomas E.
      Journal of Physical Chemistry B (2008), 112 (30), 9020-9041CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      Alkali (Li+, Na+, K+, Rb+, and Cs+) and halide (F-, Cl-, Br-, and I-) ions play an important role in many biol. phenomena, roles that range from stabilization of biomol. structure, to influence on biomol. dynamics, to key physiol. influence on homeostasis and signaling. To properly model ionic interaction and stability in atomistic simulations of biomol. structure, dynamics, folding, catalysis, and function, an accurate model or representation of the monovalent ions is critically necessary. A good model needs to simultaneously reproduce many properties of ions, including their structure, dynamics, solvation, and moreover both the interactions of these ions with each other in the crystal and in soln. and the interactions of ions with other mols. At present, the best force fields for biomols. employ a simple additive, nonpolarizable, and pairwise potential for at. interaction. In this work, the authors describe their efforts to build better models of the monovalent ions within the pairwise Coulombic and 6-12 Lennard-Jones framework, where the models are tuned to balance crystal and soln. properties in Ewald simulations with specific choices of well-known water models. Although it has been clearly demonstrated that truly accurate treatments of ions will require inclusion of nonadditivity and polarizability (particularly with the anions) and ultimately even a quantum mech. treatment, the authors' goal was to simply push the limits of the additive treatments to see if a balanced model could be created. The applied methodol. is general and can be extended to other ions and to polarizable force-field models. The authors' starting point centered on observations from long simulations of biomols. in salt soln. with the AMBER force fields where salt crystals formed well below their soly. limit. The likely cause of the artifact in the AMBER parameters relates to the naive mixing of the Smith and Dang chloride parameters with AMBER-adapted Aqvist cation parameters. To provide a more appropriate balance, the authors reoptimized the parameters of the Lennard-Jones potential for the ions and specific choices of water models. To validate and optimize the parameters, the authors calcd. hydration free energies of the solvated ions and also lattice energies (LE) and lattice consts. (LC) of alkali halide salt crystals. This is the first effort that systematically scans across the Lennard-Jones space (well depth and radius) while balancing ion properties like LE and LC across all pair combinations of the alkali ions and halide ions. The optimization across the entire monovalent series avoids systematic deviations. The ion parameters developed, optimized, and characterized were targeted for use with some of the most commonly used rigid and nonpolarizable water models, specifically TIP3P, TIP4PEW, and SPC/E. In addn. to well reproducing the soln. and crystal properties, the new ion parameters well reproduce binding energies of the ions to water and the radii of the first hydration shells.
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    36. 36
      Drew, H. R.; Dickerson, R. E. Structure of a B-DNA dodecamer. III. Geometry of hydration. J. Mol. Biol. 1981, 151, 535– 556,  DOI: 10.1016/0022-2836(81)90009-7
      36
      Structure of a B-DNA dodecamer. III. Geometry of hydration
      Drew, Horace R.; Dickerson, Richard E.
      Journal of Molecular Biology (1981), 151 (3), 535-56CODEN: JMOBAK; ISSN:0022-2836.
      The B-DNA dodecamer, C-G-C-G-A-A-T-T-C-G-C-G, crystd. as slightly more than 1 full turn of right-handed B-DNA in space group P212121 with cell dimensions a = 24.87 Å, b = 40.39 Å, and c = 66.20 Å. X-ray anal. showed that it was surrounded by 72 ordered water mols., mostly assocd. with polar N and O atoms at exposed edges of base-pairs. Hydration in the major groove was mainly in the form of a monodentate monolayer. Hydration of backbone phosphate O atoms were not ordered, except when immobilized by the 5-Me groups of adjacent thymines. The minor groove was extensively and regularly hydrated, with a zigzag spine of 1st- and 2nd-shell hydration along the floor of the groove serving as a foundation for less-regular outer shells extending beyond the radius of the phosphate backbone. The spine network bridged purine N-3 and pyrimidine O-2 atoms in adjacent base pairs; it was regular in the A-A-T-T center, but was disrupted at the C-G-C-G ends, partly by the guanine N-2 amino groups. The minor groove hydration spine may be responsible for the stability of the B form of polymers contg. only A-T and I-C base pairs, and its disruption may explain the ease of transition to the A form of polymers with G-C pairs.
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    37. 37
      Pérez, A.; Marchán, I.; Svozil, D.; Sponer, J.; Cheatham, T. E.; Laughton, C. A.; Orozco, M. Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers. Biophys. J. 2007, 92, 3817– 3829,  DOI: 10.1529/biophysj.106.097782
      37
      Refinement of the AMBER force field for nucleic acids: improving the description of α/γ conformers
      Perez, Alberto; Marchan, Ivan; Svozil, Daniel; Sponer, Jiri; Cheatham, Thomas E., III; Laughton, Charles A.; Orozco, Modesto
      Biophysical Journal (2007), 92 (11), 3817-3829CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
      We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the α/γ concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the α/γ = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mech. data and verified by comparison with very high-level quantum mech. calcns. and by a very extensive comparison between simulations and exptl. data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 μs of state-of-the-art mol. dynamics simulations in aq. soln.
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    38. 38
      Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 1981, 52, 7182– 7190,  DOI: 10.1063/1.328693
      38
      Polymorphic transitions in single crystals: A new molecular dynamics method
      Parrinello, M.; Rahman, A.
      Journal of Applied Physics (1981), 52 (12), 7182-90CODEN: JAPIAU; ISSN:0021-8979.
      A Lagrangian formulation is introduced; it can be used to make mol. dynamics (MD) calcns. on systems under the most general, externally applied, conditions of stress. In this formulation the MD cell shape and size can change according to dynamic equations given by this Lagrangian. This MD technique was used to the study of structural transitions of a Ni single crystal under uniform uniaxial compressive and tensile loads. Some results regarding the stress-strain relation obtained by static calcns. are invalid at finite temp. Under compressive loading, the model of Ni shows a bifurcation in its stress-strain relation; this bifurcation provides a link in configuration space between cubic and hexagonal close packing. Such a transition could perhaps be obsd. exptl. under extreme conditions of shock.
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    39. 39
      Kondinskaia, D. A.; Kostritskii, A. Y.; Nesterenko, A. M.; Antipina, A. Y.; Gurtovenko, A. A. Atomic-Scale Molecular Dynamics Simulations of DNA-Polycation Complexes: Two Distinct Binding Patterns. J. Phys. Chem. B 2016, 120, 6546– 6554,  DOI: 10.1021/acs.jpcb.6b03779
      39
      Atomic-Scale Molecular Dynamics Simulations of DNA-Polycation Complexes: Two Distinct Binding Patterns
      Kondinskaia, Diana A.; Kostritskii, Andrei Yu.; Nesterenko, Alexey M.; Antipina, Alexandra Yu.; Gurtovenko, Andrey A.
      Journal of Physical Chemistry B (2016), 120 (27), 6546-6554CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Synthetic cationic polymers represent a promising class of delivery vectors for gene therapy. Here, we employ atomistic mol. dynamics simulations to gain insight into the structure and properties of complexes of DNA with four linear polycations: polyethylenimine (PEI), poly-L-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). These polycations differ in their polymer geometries, protonation states, and hydrophobicities of their backbone chains. Overall, our results demonstrate for the first time the existence of two distinct patterns of binding of DNA with polycations. For PEI, PLL, and PAA, the complex is stabilized by the electrostatic attraction between protonated amine groups of the polycation and phosphate groups of DNA. In contrast, PVA demonstrates an alternative binding pattern as it gets embedded into the DNA major groove. It is likely that both the polymer topol. and affinity of the backbone chain of PVA to the DNA groove are responsible for such behavior. The differences in binding patterns can have important biomedical implications: embedding PVA into a DNA groove makes it less sensitive to changes in the aq. environment (pH level, ionic strength, etc.) and could therefore hinder the intracellular release of genetic material from a delivery vector, leading to lower transfection activity.
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    40. 40
      Michaud-Agrawal, N.; Denning, E. J.; Woolf, T. B.; Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 2011, 32, 2319– 2327,  DOI: 10.1002/jcc.21787
      40
      MDAnalysis: A toolkit for the analysis of molecular dynamics simulations
      Michaud-Agrawal, Naveen; Denning, Elizabeth J.; Woolf, Thomas B.; Beckstein, Oliver
      Journal of Computational Chemistry (2011), 32 (10), 2319-2327CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      MDAnal. is an object-oriented library for structural and temporal anal. of mol. dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-crit. code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM's powerful selection commands. MDAnal. enables both novice and experienced programmers to rapidly write their own anal. tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative anal. MDAnal. has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU General Public License from http://mdanal.googlecode.com. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011.
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    41. 41
      North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 2002, 82, 1013– 1067,  DOI: 10.1152/physrev.00015.2002
      41
      Molecular physiology of P2X receptors
      North, R. Alan
      Physiological Reviews (2002), 82 (4), 1013-1067CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
      A review. P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40-50% identical in amino acid sequence. Each subunit has two transmembrane domains, sepd. by an extracellular domain (∼280 amino acids). Channels form as multimers of several subunits. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X2/3 and P2X1/5 channels have been most fully characterized following heterologous expression. Some agonists (e.g., αβ-methylene ATP) and antagonists [e.g., 2',3'-O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors contg. P2X1 and P2X3 subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7 receptors induces a permeability increase to larger org. cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve addnl. interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The mol. compn. of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X7 receptor activation stimulates cytokine release by engaging intracellular signaling pathways.
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    42. 42
      Surprenant, A.; North, R. A. Signaling at purinergic P2X receptors. Annu. Rev. Physiol. 2009, 71, 333– 359,  DOI: 10.1146/annurev.physiol.70.113006.100630
      42
      Signaling at purinergic P2X receptors
      Surprenant, Annmarie; North, R. Alan
      Annual Review of Physiology (2009), 71 (), 333-359CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)
      A review. P2X receptors are membrane cation channels gated by extracellular ATP. Seven P2X receptor subunits (P2X1-7) are widely distributed in excitable and nonexcitable cells of vertebrates. They play key roles in inter alia afferent signaling (including pain), regulation of renal blood flow, vascular endothelium, and inflammatory responses. We summarize the evidence for these and other roles, emphasizing exptl. work with selective receptor antagonists or with knockout mice. The receptors are trimeric membrane proteins: studies of the biophys. properties of mutated subunits expressed in heterologous cells have indicated parts of the subunits involved in ATP binding, ion permeation (including calcium permeability), and membrane trafficking. We review our current understanding of the mol. properties of P2X receptors, including how this understanding is informed by the identification of distantly related P2X receptors in simple eukaryotes.
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    43. 43
      Illes, P.; Müller, C. E.; Jacobson, K. A.; Grutter, T.; Nicke, A.; Fountain, S. J.; Kennedy, C.; Schmalzing, G.; Jarvis, M. F.; Stojilkovic, S. S. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Br. J. Pharmacol. 2021, 178, 489– 514,  DOI: 10.1111/bph.15299
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      Update of P2X receptor properties and their pharmacology: IUPHAR Review 30
      Illes, Peter; Mueller, Christa E.; Jacobson, Kenneth A.; Grutter, Thomas; Nicke, Annette; Fountain, Samuel J.; Kennedy, Charles; Schmalzing, Guenther; Jarvis, Michael F.; Stojilkovic, Stanko S.; King, Brian F.; Di Virgilio, Francesco
      British Journal of Pharmacology (2021), 178 (3), 489-514CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
      A review. The known seven mammalian receptor subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystn. allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighboring subunits. In addn. to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chem. supplied a range of subtype-selective antagonists, as well as pos. and neg. allosteric modulators. Knockout mice and selective antagonists helped to identify pathol. functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).
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    44. 44
      Briones, R.; Blau, C.; Kutzner, C.; de Groot, B. L.; Aponte-Santamaría, C. Gromaρs: A Gromacs-Based Toolset to Analyse Density Maps Derived from Molecular Dynamics Simulations. Biophys. J. 2019, 116, 4– 11,  DOI: 10.1016/j.bpj.2018.11.3126
      44
      GROmaρs: A GROMACS-Based Toolset to Analyze Density Maps Derived from Molecular Dynamics Simulations
      Briones, Rodolfo; Blau, Christian; Kutzner, Carsten; de Groot, Bert L.; Aponte-Santamaria, Camilo
      Biophysical Journal (2019), 116 (1), 4-11CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      The authors introduce a computational toolset, named GROmaρs, to obtain and compare time-averaged d. maps from mol. dynamics simulations. GROmaρs efficiently computes d. maps by fast multi-Gaussian spreading of at. densities onto a three-dimensional grid. It complements existing map-based tools by enabling spatial inspection of at. av. localization during the simulations. Most importantly, it allows the comparison between computed and ref. maps (e.g., exptl.) through calcn. of difference maps and local and time-resolved global correlation. These comparison operations proved useful to quant. contrast perturbed and control simulation data sets and to examine how much biomol. systems resemble both synthetic and exptl. d. maps. This was esp. advantageous for multimol. systems in which std. comparisons like RMSDs are difficult to compute. In addn., GROmaρs incorporates abs. and relative spatial free-energy ests. to provide an energetic picture of atomistic localization. This is an open-source GROMACS-based toolset, thus allowing for static or dynamic selection of atoms or even coarse-grained beads for the d. calcn. Furthermore, masking of regions was implemented to speed up calcns. and to facilitate the comparison with exptl. maps. Beyond map comparison, GROmaρs provides a straightforward method to detect solvent cavities and av. charge distribution in biomol. systems. The authors employed all these functionalities to inspect the localization of lipid and water mols. in aquaporin systems, the binding of cholesterol to the G protein coupled chemokine receptor type 4, and the identification of permeation pathways through the dermicidin antimicrobial channel. Based on these examples, the authors anticipate a high applicability of GROmaρs for the anal. of mol. dynamics simulations and their comparison with exptl. detd. densities.
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    45. 45
      Chen, X.; Bründl, M.; Friesacher, T.; Stary-Weinzinger, A. Computational Insights Into Voltage Dependence of Polyamine Block in a Strong Inwardly Rectifying K+ Channel. Front. Pharmacol. 2020, 11, 721  DOI: 10.3389/fphar.2020.00721
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      Computational insights into voltage dependence of polyamine block in a strong inwardly rectifying K+ channel
      Chen, Xingyu; Bruendl, Michael; Friesacher, Theres; Stary-Weinzinger, Anna
      Frontiers in Pharmacology (2020), 11 (), 00721CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      Inwardly rectifying potassium (KIR) channels play important roles in controlling cellular excitability and K+ ion homeostasis. Under physiol. conditions, KIR channels allow large K+ influx at potentials neg. to the equil. potential of K+ but permit little outward current at potentials pos. to the equil. potential of K+, due to voltage dependent block of outward K+ flux by cytoplasmic polyamines. These polycationic mols. enter the KIR channel pore from the intracellular side. They block K+ ion movement through the channel at depolarized potentials, thereby ensuring, for instance, the long plateau phase of the cardiac action potential. Key questions concerning how deeply these charged mols. migrate into the pore and how the steep voltage dependence arises remain unclear. Recent MD simulations on GIRK2 (=Kir3.2) crystal structures have provided unprecedented details concerning the conduction mechanism of a KIR channel. Here, we use MD simulations with applied field to provide detailed insights into voltage dependent block of putrescine, using the conductive state of the strong inwardly rectifying K+ channel GIRK2 as starting point. Our μs long simulations elucidate details about binding sites of putrescine in the pore and suggest that voltage dependent rectification arises from a dual mechanism.
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    46. 46
      Nyblom, M.; Frick, A.; Wang, Y.; Ekvall, M.; Hallgren, K.; Hedfalk, K.; Neutze, R.; Tajkhorshid, E.; Törnroth-Horsefield, S. Structural and functional analysis of SoPIP2;1 mutants adds insight into plant aquaporin gating. J. Mol. Biol. 2009, 387, 653– 668,  DOI: 10.1016/j.jmb.2009.01.065
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      Structural and Functional Analysis of SoPIP2;1 Mutants Adds Insight into Plant Aquaporin Gating
      Nyblom, Maria; Frick, Anna; Wang, Yi; Ekvall, Mikael; Hallgren, Karin; Hedfalk, Kristina; Neutze, Richard; Tajkhorshid, Emad; Toernroth-Horsefield, Susanna
      Journal of Molecular Biology (2009), 387 (3), 653-668CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
      Plant plasma membrane aquaporins facilitate water flux into and out of plant cells, thus coupling their cellular function to basic aspects of plant physiol. Posttranslational modifications of conserved phosphorylation sites, changes in cytoplasmic pH, and the binding of Ca2+ can regulate water transport activity by gating the plasma membrane aquaporins. A structural mechanism unifying these diverse biochem. signals has emerged for the spinach aquaporin SoPIP2;1, although several questions concerning the opening mechanism remain. Here, we describe the X-ray structures of the S115E and S274E single SoPIP2;1 mutants and the corresponding double mutant. Phosphorylation of these serines is believed to increase water transport activity of SoPIP2;1 by opening the channel. However, all mutants crystd. in a closed conformation, as confirmed by water transport assays, implying that neither substitution fully mimics the phosphorylated state. Nevertheless, a half-turn extension of transmembrane helix 1 occurs upon the substitution of Ser115, which draws the Cα atom of Glu31 10 Å away from its wild-type conformation, thereby disrupting the divalent cation binding site involved in the gating mechanism. Mutation of Ser274 disorders the C-terminus but no other significant conformational changes are obsd. Inspection of the hydrogen-bond interactions within loop D suggested that the phosphorylation of Ser188 may also produce an open channel, and this was supported by an increased water transport activity for the S188E mutant and mol. dynamics simulations. These findings add addnl. insight into the general mechanism of plant aquaporin gating.
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    47. 47
      Ruiz, L.; Wu, Y.; Keten, S. Tailoring the water structure and transport in nanotubes with tunable interiors. Nanoscale 2015, 7, 121– 132,  DOI: 10.1039/C4NR05407E
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      Tailoring the water structure and transport in nanotubes with tunable interiors
      Ruiz, Luis; Wu, Yuanqiao; Keten, Sinan
      Nanoscale (2015), 7 (1), 121-132CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Self-assembly of cyclic peptide nanotubes (CPNs) in polymer thin films has opened up the possibility of creating sepn. membranes with tunable nanopores that can differentiate mols. at the sub-nanometer level. While it has been demonstrated that the interior chem. of the CPNs can be tailored by inserting functional groups in the nanopore lumen (mCPNs), a design strategy for picking the chem. modifications that lead to particular transport properties has not been established. Drawing from the knowledgebase of functional groups in natural amino acids, here we use mol. dynamics simulations to elucidate how bioinspired mutations influence the transport of water through mCPNs. We show that, at the nanoscale, factors besides the pore size, such as electrostatic interactions and steric effects, can dramatically change the transport properties. We recognize a novel asym. structure of water under nanoconfinement inside the chem. functionalized nanotubes and identify that the small non-polar glycine-mimic groups that minimize the steric constraints and confer a hydrophobic character to the nanotube interior are the fastest transporters of water. Our computationally developed expts. on a realistic material system circumvent synthetic challenges, and lay the foundation for bioinspired principles to tailor artificial nanochannels for sepn. applications such as desalination, ion-exchange and carbon capture.
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    48. 48
      Kasimova, M. A.; Lindahl, E.; Delemotte, L. Determining the molecular basis of voltage sensitivity in membrane proteins. J. Gen. Physiol. 2018, 150, 1444– 1458,  DOI: 10.1085/jgp.201812086
      48
      Determining the molecular basis of voltage sensitivity in membrane proteins
      Kasimova, Marina A.; Lindahl, Erik; Delemotte, Lucie
      Journal of General Physiology (2018), 150 (10), 1444-1458CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
      Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mech. work. They are responsible for a spectrum of physiol. processes in living organisms, including elec. signaling and cell-cycle progression. Moreover, the detection of these elements by using exptl. techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estn. of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis expts. will significantly reduce the no. of potential voltage-sensitive elements to be tested.
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    49. 49
      Scheurer, M.; Rodenkirch, P.; Siggel, M.; Bernardi, R. C.; Schulten, K.; Tajkhorshid, E.; Rudack, T. PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations. Biophys. J. 2018, 114, 577– 583,  DOI: 10.1016/j.bpj.2017.12.003
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      PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations
      Scheurer, Maximilian; Rodenkirch, Peter; Siggel, Marc; Bernardi, Rafael C.; Schulten, Klaus; Tajkhorshid, Emad; Rudack, Till
      Biophysical Journal (2018), 114 (3), 577-583CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      Mol. dynamics (MD) simulations have become ubiquitous in all areas of life sciences. The size and model complexity of MD simulations are rapidly growing along with increasing computing power and improved algorithms. This growth gave a large amt. of simulation data that need to be filtered for relevant information to address specific biomedical and biochem. questions. One of the most relevant mol. properties that can be studied by all-atom MD simulations is the time-dependent evolution of the complex noncovalent interaction networks governing such fundamental aspects as mol. recognition, binding strength, and mech. and structural stability. Extg., evaluating, and visualizing noncovalent interactions is a key task in the daily work of structural biologists. The authors have developed PyContact, an easy-to-use, highly flexible, and intuitive graphical user interface-based application, designed to provide a toolkit to study biomol. interactions in MD trajectories. PyContact is designed to facilitate this task by enabling identification of relevant noncovalent interactions in a comprehensible manner. The implementation of PyContact as a standalone application enables rapid anal. and data visualization without any addnl. programming requirements, and also preserves full in-program customization and extension capabilities for advanced users. The statistical anal. representation is interactively combined with full mapping of the results on the mol. system through the synergistic connection between PyContact and VMD. The authors showcase the capabilities and scientific significance of PyContact by analyzing and visualizing in great detail the noncovalent interactions underlying the ion permeation pathway of the human P2X3 receptor. As a second application, the authors examine the protein-protein interaction network of the mech. ultrastable cohesin-dockering complex.
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    50. 50
      Melcr, J.; Martinez-Seara, H.; Nencini, R.; Kolafa, J.; Jungwirth, P.; Ollila, O. H. S. Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization. J. Phys. Chem. B 2018, 122, 4546– 4557,  DOI: 10.1021/acs.jpcb.7b12510
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      Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization
      Melcr, Josef; Martinez-Seara, Hector; Nencini, Ricky; Kolafa, Jiri; Jungwirth, Pavel; Ollila, O. H. Samuli
      Journal of Physical Chemistry B (2018), 122 (16), 4546-4557CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Binding affinities and stoichiometries of Na+ and Ca2+ ions to phospholipid bilayers are of paramount significance in the properties and functionality of cellular membranes. Current ests. of binding affinities and stoichiometries of cations are, however, inconsistent due to limitations in the available exptl. and computational methods. In this work, the authors improve the description of the binding details of Na+ and Ca2+ ions to a 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) bilayer by implicitly including electronic polarization as a mean field correction, known as the electronic continuum correction (ECC). This is applied by scaling the partial charges of a selected state-of-the-art POPC lipid model for mol. dynamics simulations. The improved ECC-POPC model reproduces not only the exptl. measured structural parameters for the ion-free membrane, but also the response of lipid headgroup to a strongly bound cationic amphiphile, as well as the binding affinities of Na+ and Ca2+ ions. With the new model, the authors observe on the one side negligible binding of Na+ ions to POPC bilayer, while on the other side stronger interactions of Ca2+ primarily with phosphate oxygens, which is in agreement with the previous interpretations of the exptl. spectroscopic data. The present model results in Ca2+ ions forming complexes with one to three POPC mols. with almost equal probabilities, suggesting more complex binding stoichiometries than those from simple models used to interpret the NMR data previously. The results of this work pave the way to quant. mol. simulations with realistic electrostatic interactions of complex biochem. systems at cellular membranes.
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    51. 51
      Melcrová, A.; Pokorna, S.; Pullanchery, S.; Kohagen, M.; Jurkiewicz, P.; Hof, M.; Jungwirth, P.; Cremer, P. S.; Cwiklik, L. The complex nature of calcium cation interactions with phospholipid bilayers. Sci. Rep. 2016, 6, 38035  DOI: 10.1038/srep38035
      51
      The complex nature of calcium cation interactions with phospholipid bilayers
      Melcrova, Adela; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz
      Scientific Reports (2016), 6 (), 38035CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Understanding interactions of calcium with lipid membranes at the mol. level is of great importance in light of their involvement in calcium signaling, assocn. of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic mol. dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-contg. environments. To gain addnl. at.-level information, the expts. are complemented by mol. simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concn. with important implications for calcium buffering, synaptic plasticity, and protein-membrane assocn.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFWnsr7F&md5=a4be8d96f3217f88b2ab791199726e08
    52. 52
      Burnstock, G. Purinergic signalling and disorders of the central nervous system. Nat. Rev. Drug Discovery 2008, 7, 575– 590,  DOI: 10.1038/nrd2605
      52
      Purinergic signaling and disorders of the central nervous system
      Burnstock, Geoffrey
      Nature Reviews Drug Discovery (2008), 7 (7), 575-590CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. There is increasing interest in the role of purinergic signaling in CNS disorders, but few modulators have reached the clinic. Here, Burnstock provides an overview of the role of purinergic signaling in specific disorders, including brain trauma, ischemia, neurodegenerative, neuroinflammatory and neuropsychiatric diseases, and highlights specific purinergic receptor subtypes that represent promising therapeutic targets. Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathol. conditions including brain trauma and ischemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signaling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A2A, P2X4 and P2X7, that might be therapeutically targeted for the treatment of these conditions.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvFShtrs%253D&md5=95a3c406c113eec093fd5437e98ee49e
    53. 53
      Pomorski, T.; Menon, A. K. Lipid flippases and their biological functions. Cell. Mol. Life Sci. 2006, 63, 2908– 2921,  DOI: 10.1007/s00018-006-6167-7
      53
      Lipid flippases and their biological functions
      Pomorski, T.; Menon, A. K.
      Cellular and Molecular Life Sciences (2006), 63 (24), 2908-2921CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
      A review. The typically distinct phospholipid compn. of the 2 leaflets of a membrane bilayer is generated and maintained by bi-directional transport (flip-flop) of lipids between the leaflets. Specific membrane proteins, termed lipid flippases, play an essential role in this transport process. Energy-independent flippases allow common phospholipids to equilibrate rapidly between the two monolayers and also play a role in the biosynthesis of a variety of glycoconjugates such as glycosphingolipids, N-glycoproteins, and glycosylphosphatidylinositol (GPI)-anchored proteins. ATP-dependent flippases, including members of a conserved subfamily of P-type ATPases and ATP-binding cassette transporters, mediate the net transfer of specific phospholipids to one leaflet of a membrane and are involved in the creation and maintenance of transbilayer lipid asymmetry of membranes such as the plasma membrane of eukaryotes. Energy-dependent flippases also play a role in the biosynthesis of glycoconjugates such as bacterial lipopolysaccharide. Here, the authors summarize recent progress on the identification and characterization of the various flippases and the demonstration of their biol. functions.
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    54. 54
      Jiang, T.; Yu, K.; Hartzell, H. C.; Tajkhorshid, E. Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase. eLife 2017, 6, e28671  DOI: 10.7554/eLife.28671
      54
      Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase
      Jiang, Tao; Yu, Kuai; Hartzell, H. Criss; Tajkhorshid, Emad
      eLife (2017), 6 (), e28671/1-e28671/26CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
      From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with exptl. assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helixes that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase.
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    55. 55
      Bethel, N. P.; Grabe, M. Atomistic insight into lipid translocation by a TMEM16 scramblase. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 14049– 14054,  DOI: 10.1073/pnas.1607574113
      55
      Atomistic insight into lipid translocation by a TMEM16 scramblase
      Bethel, Neville P.; Grabe, Michael
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (49), 14049-14054CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The transmembrane protein 16 (TMEM16) family of membrane proteins includes both lipid scramblases and ion channels involved in olfaction, nociception, and blood coagulation. The crystal structure of the fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase suggested a putative mechanism of lipid transport, whereby polar and charged lipid headgroups move through the low-dielec. environment of the membrane by traversing a hydrophilic groove on the membrane-spanning surface of the protein. Here, we use computational methods to explore the membrane-protein interactions involved in lipid scrambling. Fast, continuum membrane-bending calcns. reveal a global pattern of charged and hydrophobic surface residues that bends the membrane in a large-amplitude sinusoidal wave, resulting in bilayer thinning across the hydrophilic groove. Atomic simulations uncover two lipid headgroup-interaction sites flanking the groove. The cytoplasmic site nucleates headgroup-dipole stacking interactions that form a chain of lipid mols. that penetrate into the groove. In two instances, a cytoplasmic lipid interdigitates into this chain, crosses the bilayer, and enters the extracellular leaflet, and the reverse process happens twice as well. Continuum membrane-bending anal. carried out on homol. models of mammalian homologs shows that these family members also bend the membrane-even those that lack scramblase activity. Sequence alignments show that the lipid-interaction sites are conserved in many family members but less so in those with reduced scrambling ability. Our anal. provides insight into how large-scale membrane bending and protein chem. facilitate lipid permeation in the TMEM16 family, and we hypothesize that membrane interactions also affect ion permeation.
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    56. 56
      Pedemonte, N.; Galietta, L. J. V. Structure and function of TMEM16 proteins (anoctamins). Physiol. Rev. 2014, 94, 419– 459,  DOI: 10.1152/physrev.00039.2011
      56
      Structure and function of TMEM16 proteins (anoctamins)
      Pedemonte, Nicoletta; Galietta, Luis J. V.
      Physiological Reviews (2014), 94 (2), 419-459CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
      A review. TMEM16 proteins, also known as anoctamins, are involved in a variety of functions that include ion transport, phospholipid scrambling, and regulation of other membrane proteins. The first two members of the family, TMEM16A (anoctamin-1, AN01) and TMEM16B (anoctamin-2, AN02), function as Ca2+-activated Cl- channels (CaCCs), a type of ion channel that plays important functions such as transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception, and control of neuronal excitability. Genetic ablation of TMEM16A in mice causes impairment of epithelial Cl- secretion, tracheal abnormalities, and block of gastrointestinal peristalsis. TMEM16A is directly regulated by cytosolic Ca2+ as well as indirectly by its interaction with calmodulin. Other members of the anoctamin family, such as TMEM16C, TMEM16D, TMEM16F, TMEM16G, and TMEM16J, may work as phospholipid scramblases and/or ion channels. In particular, TMEM16F (AN06) is a major contributor to the process of phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane. Intriguingly, TMEM16F is also assocd. with the appearance of anion/cation channels activated by very high Ca2+ concns. Furthermore, a TMEM16 protein expressed in Aspergillus fumigatus displays both ion channel and lipid scramblase activity. This finding suggests that dual function is an ancestral characteristic of TMEM16 proteins and that some members, such as TMEM16A and TMEM16B, have evolved to a pure channel function. Mutations in anoctamin genes (AN03, AN05, AN06, and AN010) cause various genetic diseases. These diseases suggest the involvement of anoctamins in a variety of cell functions whose link with ion transport and/or lipid scrambling needs to be clarified.
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    57. 57
      Kalienkova, V.; Clerico Mosina, V.; Bryner, L.; Oostergetel, G. T.; Dutzler, R.; Paulino, C. Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM. eLife 2019, 8, e44364  DOI: 10.7554/eLife.44364
      57
      Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo- EM
      Kalienkova, Valeria; Mosina, Vanessa Clerico; Bryner, Laura; Oostergetel, Gert T.; Dutzler, Raimund; Paulino, Cristina
      eLife (2019), 8 (), 44364CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
      Scramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca2+ binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca2+-bound state. Addnl., our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.
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    58. 58
      Falzone, M. E.; Rheinberger, J.; Lee, B.-C.; Peyear, T.; Sasset, L.; Raczkowski, A. M.; Eng, E. T.; Di Lorenzo, A.; Andersen, O. S.; Nimigean, C. M.; Accardi, A. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. eLife 2019, 8, e43229  DOI: 10.7554/eLife.43229
      58
      Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase
      Falzone, Maria E.; Rheinberger, Jan; Lee, Byoung-Cheol; Peyear, Thasin; Sasset, Linda; Raczkowski, Ashleigh M.; Eng, Edward T.; Lorenzo, Annarita Di; Andersen, Olaf S.; Nimigean, Crina M.; Accardi, Alessio
      eLife (2019), 8 (), 43229CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
      The lipid distribution of plasma membranes of eukaryotic cells is asym. and phospholipid scramblases disrupt this asymmetry by mediating the rapid, nonselective transport of lipids down their concn. gradients. As a result, phosphatidylserine is exposed to the outer leaflet of membrane, an important step in extracellular signaling networks controlling processes such as apoptosis, blood coagulation, membrane fusion and repair. Several TMEM16 family members have been identified as Ca2+-activated scramblases, but the mechanisms underlying their Ca2+-dependent gating and their effects on the surrounding lipid bilayer remain poorly understood. Here, we describe three high-resoln. cryo-electron microscopy structures of a fungal scramblase from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs. These structures reveal that Ca2+-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. These structures, together with functional expts., suggest that activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVegtLvK&md5=bf21156b76417f26aa25c95a6203cfa2
    59. 59
      Feng, S.; Dang, S.; Han, T. W.; Ye, W.; Jin, P.; Cheng, T.; Li, J.; Jan, Y. N.; Jan, L. Y.; Cheng, Y. Cryo-EM studies of TMEM16F Calcium-Activated ion channel suggest features important for lipid scrambling. Cell Rep. 2019, 28, 567– 579,  DOI: 10.1016/j.celrep.2019.06.023
      59
      Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling
      Feng, Shengjie; Dang, Shangyu; Han, Tina Wei; Ye, Wenlei; Jin, Peng; Cheng, Tong; Li, Junrui; Jan, Yuh Nung; Jan, Lily Yeh; Cheng, Yifan
      Cell Reports (2019), 28 (2), 567-579.e4CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      As a Ca2+-activated lipid scramblase and ion channel that mediates Ca2+ influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca2+ influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest sep. pathways for lipid scrambling and ion permeation.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlGjtrjI&md5=be585b9b50fc27815a33b0aae7de9bdb
    60. 60
      Alvadia, C.; Lim, N. K.; Clerico Mosina, V.; Oostergetel, G. T.; Dutzler, R.; Paulino, C. Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. eLife 2019, 8, e44365  DOI: 10.7554/eLife.44365
      60
      Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F
      Alvadia, Carolina; Lim, Novandy K.; Mosina, Vanessa Clerico; Oostergetel, Gert T.; Dutzler, Raimund; Paulino, Cristina
      eLife (2019), 8 (), 44365CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
      The lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of murine TMEM16F (mTMEM16F) that underlie its function as a lipid scramblase and an ion channel. The cryo-EM data of mTMEM16F in absence and presence of Ca2+ define the ligand-free closed conformation of the protein and the structure of a Ca2+-bound intermediate. Both conformations resemble their counterparts of the scrambling-incompetent anion channel mTMEM16A, yet with distinct differences in the region of ion and lipid permeation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, both functions appear to be mediated by alternate protein conformations that are at equil. in the ligand-bound state.
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    61. 61
      Lim, N. K.; Lam, A. K.; Dutzler, R. Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A. J. Gen. Physiol. 2016, 148, 375– 392,  DOI: 10.1085/jgp.201611650
      61
      Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A
      Lim, Novandy K.; Lam, Andy K. M.; Dutzler, Raimund
      Journal of General Physiology (2016), 148 (5), 375-392, S19-S20CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
      The TMEM16 proteins constitute a family of membrane proteins with unusual functional breadth, including lipid scramblases and Cl- channels. Members of both these branches are activated by Ca2+, acting from the intracellular side, and probably share a common architecture, which was defined in the recent structure of the lipid scramblase nhTMEM16. The structural features of subunits and the arrangement of Ca2+-binding sites in nhTMEM16 suggest that the dimeric protein harbors two locations for catalysis that are independent with respect to both activation and lipid conduction. Here, we ask whether a similar independence is obsd. in the Ca2+-activated Cl- channel TMEM16A. For this purpose, we generated concatenated constructs contg. subunits with distinct activation and permeation properties. Our biochem. investigations demonstrate the integrity of concatemers after solubilization and purifn. During investigation by patch-clamp electrophysiol., the functional behavior of constructs contg. either two wild-type (WT) subunits or one WT subunit paired with a second subunit with compromised activation closely resembles TMEM16A. This resemblance extends to ion selectivity, conductance, and the concn. and voltage dependence of channel activation by Ca2+. Constructs combining subunits with different potencies for Ca2+ show a biphasic activation curve that can be described as a linear combination of the properties of its constituents. The functional independence is further supported by mutation of a putative pore-lining residue that changes the conduction properties of the mutated subunit. Our results strongly suggest that TMEM16A contains two ion conduction pores that are independently activated by Ca2+ binding to sites that are embedded within the transmembrane part of each subunit.
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    62. 62
      Jeng, G.; Aggarwal, M.; Yu, W.-P.; Chen, T.-Y. Independent activation of distinct pores in dimeric TMEM16A channels. J. Gen. Physiol. 2016, 148, 393– 404,  DOI: 10.1085/jgp.201611651
      62
      Independent activation of distinct pores in dimeric TMEM16A channels
      Jeng, Grace; Aggarwal, Muskaan; Yu, Wei-Ping; Chen, Tsung-Yu
      Journal of General Physiology (2016), 148 (5), 393-404, S13-S14CODEN: JGPLAD; ISSN:1540-7748. (Rockefeller University Press)
      The TMEM16 family encompasses Ca2+-activated Cl- channels (CaCCs) and lipid scramblases. These proteins are formed by two identical subunits, as confirmed by the recently solved crystal structure of a TMEM16 lipid scram-blase. However, the high-resoln. structure did not provide definitive information regarding the pore architecture of the TMEM16 channels. In this study, we express TMEM16A channels constituting two covalently linked subunits with different Ca2+ affinities. The dose-response curve of the heterodimer appears to be a weighted sum of two dose-response curves-one corresponding to the high-affinity subunit and the other to the low-affinity subunit. However, fluorescence resonance energy transfer expts. suggest that the covalently linked heterodimeric proteins fold and assemble as one mol. Together these results suggest that activation of the two TMEM16A subunits likely activate independently of each other. The Ca2+ activation curve for the heterodi-mer at a low Ca2+ concn. range ([Ca2+] < 5μM) is similar to that of the wild-type channel-the Hill coeffs. in both cases are significantly greater than one. This suggests that Ca2+ binding to one subunit of TMEM16A is sufficient to activate the channel and that each subunit contains more than one Ca2+-binding site. We also take advantage of the I-V curve rectification that results from mutation of a pore residue to address the pore architec-ture of the channel. By introducing the pore mutation and the mutation that alters Ca2+ affinity in the same or different subunits, we demonstrate that activation of different subunits appears to be assocd. with the opening of different pores. These results suggest that the TMEM16A CaCC may also adopt a"double-barrel"pore architecture, similar to that found in CLC channels and transporters.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkvF2qtrk%253D&md5=72fcb349ae446a73a14d16604751294a
    63. 63
      Kanner, B. I.; Bendahan, A. Binding order of substrates to the (sodium + potassium ion)-coupled L-glutamic acid transporter from rat brain. Biochemistry 1982, 21, 6327– 6330,  DOI: 10.1021/bi00267a044
      63
      Binding order of substrates to the (sodium + potassium ion)-coupled L-glutamic acid transporter from rat brain
      Kanner, Baruch I.; Bendahan, Annie
      Biochemistry (1982), 21 (24), 6327-30CODEN: BICHAW; ISSN:0006-2960.
      Efflux of L-glutamic acid (I) [7440-23-5] from rat brain synaptic plasm membrane vesicles requires external K+. This requirement is satd. by concns. of ∼15 mequiv/L K+. In the absence of K+, I can be released from the vesicles in the presence of external I. This stimulation does not require external Na+ but is dependent on the external concn. of I. Half-maximal effects are obtained by concns. of ∼1 μM which are very similar to the apparent Km for I influx. Efflux of labeled I driven by external Na+ plus I requires internal Na+. The transporter apparently displays an asym. behavior toward Na+. This ion dissocs. much more slowly than does I on the external surface of the membrane but not on the internal surface. Furthermore, the transporter apparently translocates K+ in a step distinct from the I translocation step. The simplest explanation is that upon translocation of Na+ and I and their release to the inside, K+ binds to the transporter, enabling it to return to the outside to allow initiation of a new transport cycle.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XlvFelsLo%253D&md5=2ff713407683ab142203cc789e4a3b61
    64. 64
      Zerangue, N.; Kavanaugh, M. P. Flux coupling in a neuronal glutamate transporter. Nature 1996, 383, 634– 637,  DOI: 10.1038/383634a0
      64
      Flux coupling in a neuronal glutamate transporter
      Zerangue, Noa; Kavanaugh, Michael P.
      Nature (London) (1996), 383 (6601), 634-637CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)
      Synaptic transmission is commonly terminated by diffusion and reuptake of neurotransmitter from the synaptic cleft. Glutamate reuptake prevents neurotoxicity and sets the lower limit for the concn. of extracellular glutamate, so it is important to understand the thermodn. of this process. Here we use voltage clamping with a pH-sensitive fluorescent dye to monitor elec. currents and pH changes assocd. with flux of glutamate mediated by the human neuronal glutamate transporter EAAT3. In contrast to a previous model, we find that three sodium ions and one proton are cotransported with each glutamate ion into the cell, while one potassium ion is transported out of the cell. This coupling can support a transmembrane glutamate concn. gradient ([Glu]in/[Glu]out) exceeding 106 under equil. conditions, and would allow the transporter to continue removing glutamate over a wide range of ionic conditions.
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    65. 65
      Vandenberg, R. J.; Ryan, R. M. Mechanisms of Glutamate Transport. Physiol. Rev. 2013, 93, 1621– 1657,  DOI: 10.1152/physrev.00007.2013
      65
      Mechanisms of glutamate transport
      Vandenberg, Robert J.; Ryan, Renae M.
      Physiological Reviews (2013), 93 (4), 1621-1657CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
      A review. L-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurol. disorders. The control of glutamate concns. is crit. to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concns. to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystd. and its structure detd. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.
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    66. 66
      Machtens, J.-P.; Kortzak, D.; Lansche, C.; Leinenweber, A.; Kilian, P.; Begemann, B.; Zachariae, U.; Ewers, D.; de Groot, B. L.; Briones, R.; Fahlke, C. Mechanisms of anion conduction by coupled glutamate transporters. Cell 2015, 160, 542– 553,  DOI: 10.1016/j.cell.2014.12.035
      66
      Mechanisms of anion conduction by coupled glutamate transporters
      Machtens, Jan-Philipp; Kortzak, Daniel; Lansche, Christine; Leinenweber, Ariane; Kilian, Petra; Begemann, Birgit; Zachariae, Ulrich; Ewers, David; de Groot, Bert L.; Briones, Rodolfo; Fahlke, Christoph
      Cell (Cambridge, MA, United States) (2015), 160 (3), 542-553CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Excitatory amino acid transporters (EAATs) are essential for terminating glutamatergic synaptic transmission. They are not only coupled glutamate/Na+/H+/K+ transporters, but they also function as anion-selective channels. EAAT anion channels regulate neuronal excitability, and gain-of-function mutations in these proteins result in ataxia and epilepsy. Here, the authors combined mol. dynamics simulations with fluorescence spectroscopy of prokaryotic homolog glutamate transporter GltPh and patch-clamp recordings of mammalian EAATs to det. how these transporters conduct anions. Whereas outward- and inward-facing GltPh conformations were nonconductive, lateral movement of the glutamate transport domain from intermediate transporter conformations resulted in the formation of an anion-selective conduction pathway. Fluorescence quenching of inserted Trp residues indicated the entry of anions into this pathway, and mutations of homologous pore-forming residues had analogous effects on GltPh simulations and EAAT2/EAAT4 measurements of single-channel currents and anion/cation selectivities. These findings provided a mechanistic framework of how neurotransmitter transporters can operate as anion-selective and ligand-gated ion channels.
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    67. 67
      Bastug, T.; Heinzelmann, G.; Kuyucak, S.; Salim, M.; Vandenberg, R. J.; Ryan, R. M. Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1. PLoS One 2012, 7, e33058  DOI: 10.1371/journal.pone.0033058
      67
      Position of the third Na+ site in the Aspartate transporter GltPh and the human glutamate transporter, EAAT1
      Bastug, Turgut; Heinzelmann, Germano; Kuyucak, Serdar; Salim, Marietta; Vandenberg, Robert J.; Ryan, Renae M.
      PLoS One (2012), 7 (3), e33058CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na+ ions, one H+ and the counter-transport of one K+ ion. Transport by an archaeal homolog of the human glutamate transporters, GltPh, whose three dimensional structure is known is also coupled to three Na+ ions but only two Na+ ion binding sites have been obsd. in the crystal structure of GltPh. In order to fully utilize the GltPh structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of GltPh and accurately det. the no. and location of Na+ ions coupled to transport. Several sites have been proposed for the binding of a third Na+ ion from electrostatic calcns. and mol. dynamics simulations. In this study, we have performed detailed free energy simulations for GltPh and reveal a new site for the third Na+ ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in GltPh, and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na+ compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na+ ion in GltPh and EAAT1.
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    68. 68
      Kortzak, D.; Alleva, C.; Weyand, I.; Ewers, D.; Zimmermann, M. I.; Franzen, A.; Machtens, J.-P.; Fahlke, C. Allosteric gate modulation confers K+ coupling in glutamate transporters. EMBO J. 2019, 38, e101468  DOI: 10.15252/embj.2019101468
      There is no corresponding record for this reference.
    69. 69
      Setiadi, J.; Kuyucak, S. Free-Energy Simulations Resolve the Low-Affinity Na+-High-Affinity Asp Binding Paradox in GltPh. Biophys. J. 2019, 117, 780– 789,  DOI: 10.1016/j.bpj.2019.07.016
      69
      Free-Energy Simulations Resolve the Low-Affinity Na+-High-Affinity Asp Binding Paradox in GltPh
      Setiadi, Jeffry; Kuyucak, Serdar
      Biophysical Journal (2019), 117 (4), 780-789CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      Glutamate transporters clear up excess extracellular glutamate by cotransporting three Na+ and one H+ with the countertransport of one K+. The archaeal homologs are selective to aspartate and only cotransport three Na+. The crystal structures of GltPh from archaea have been used in computational studies to understand the transport mechanism. Although some progress has been made with regard to the ligand-binding sites, a consistent picture of transport still eludes us. A major concern is the discrepancy between the computed binding free energies, which predict high-affinity Na+-low-affinity aspartate binding, and the exptl. results in which the opposite is obsd. Here, we show that the binding of the first two Na+ ions involves an intermediate state near the Na1 site, where two Na+ ions coexist and couple to aspartate with similar strengths, boosting its affinity. Binding free energies for Na+ and aspartate obtained using this intermediate state are in good agreement with the exptl. values. Thus, the paradox in binding affinities arises from the assumption that the ligands bind to the sites obsd. in the crystal structure following the order dictated by their binding free energies with no intermediate states. In fact, the presence of an intermediate state eliminates such a correlation between the binding free energies and the binding order. The intermediate state also facilitates transition of the first Na+ ion to its final binding site via a knock-on mechanism, which induces substantial conformational changes in the protein consistent with exptl. observations.
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    70. 70
      Machtens, J.-P.; Briones, R.; Alleva, C.; de Groot, B. L.; Fahlke, C. Gating Charge Calculations by Computational Electrophysiology Simulations. Biophys. J. 2017, 112, 1396– 1405,  DOI: 10.1016/j.bpj.2017.02.016
      70
      Gating Charge Calculations by Computational Electrophysiology Simulations
      Machtens, Jan-Philipp; Briones, Rodolfo; Alleva, Claudia; de Groot, Bert L.; Fahlke, Christoph
      Biophysical Journal (2017), 112 (7), 1396-1405CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      Elec. cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the mol. details of voltage sensing remain insufficiently understood. Here, we present a mol. dynamics simulation-based method to det. the underlying charge movement across the membrane-the gating charge-by measuring elec. capacitor properties of membrane-embedded proteins. We illustrate the approach by calcg. the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1.2 K+ channel and the voltage sensor of the Ciona intestinalis voltage-sensitive phosphatase, against exptl. data. We then use the gating charge anal. to study how the T1 domain modifies voltage sensing in Kv1.2 channels and to investigate the voltage dependence of the initial binding of two Na+ ions in Na+-coupled glutamate transporters. Our simulation approach quantifies various mechanisms of voltage sensing, enables direct comparison with expts., and supports mechanistic interpretation of voltage sensitivity by fractional amino acid contributions.
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    71. 71
      Groeneveld, M.; Slotboom, D.-J. Na+:Aspartate Coupling Stoichiometry in the Glutamate Transporter Homologue GltPh. Biochemistry 2010, 49, 3511– 3513,  DOI: 10.1021/bi100430s
      71
      Na+:Aspartate Coupling Stoichiometry in the Glutamate Transporter Homologue GltPh
      Groeneveld, Maarten; Slotboom, Dirk-Jan
      Biochemistry (2010), 49 (17), 3511-3513CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      The Na+ aspartate symporter GltPh from Pyrococcus horikoshii is the only member of the glutamate transporter family for which crystal structures have been detd. The cation:aspartate coupling stoichiometry is unknown, thus hampering the elucidation of the ion coupling mechanism. Here we measure transport of 22Na+ and [14C]aspartate in proteoliposomes contg. purified GltPh and demonstrate that three Na+ ions are symported with aspartate.
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    72. 72
      Samal, S. K.; Dash, M.; Van Vlierberghe, S.; Kaplan, D. L.; Chiellini, E.; van Blitterswijk, C.; Moroni, L.; Dubruel, P. Cationic polymers and their therapeutic potential. Chem. Soc. Rev. 2012, 41, 7147– 7194,  DOI: 10.1039/c2cs35094g
      72
      Cationic polymers and their therapeutic potential
      Samal, Sangram Keshari; Dash, Mamoni; Van Vlierberghe, Sandra; Kaplan, David L.; Chiellini, Emo; van Blitterswijk, Clemens; Moroni, Lorenzo; Dubruel, Peter
      Chemical Society Reviews (2012), 41 (21), 7147-7194CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. The last decade has witnessed enormous research focused on cationic polymers. Cationic polymers are the subject of intense research as non-viral gene delivery systems, due to their flexible properties, facile synthesis, robustness and proven gene delivery efficiency. Here, the authors review the most recent scientific advances in cationic polymers and their derivs. not only for gene delivery purposes but also for various alternative therapeutic applications. An overview of the synthesis and prepn. of cationic polymers is provided along with their inherent bioactive and intrinsic therapeutic potential. In addn., cationic polymer based biomedical materials are covered. Major progress in the fields of drug and gene delivery as well as tissue engineering applications is summarized in the present review.
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    73. 73
      Kostritskii, A. Y.; Kondinskaia, D. A.; Nesterenko, A. M.; Gurtovenko, A. A. Adsorption of Synthetic Cationic Polymers on Model Phospholipid Membranes: Insight from Atomic-Scale Molecular Dynamics Simulations. Langmuir 2016, 32, 10402– 10414,  DOI: 10.1021/acs.langmuir.6b02593
      73
      Adsorption of Synthetic Cationic Polymers on Model Phospholipid Membranes: Insight from Atomic-Scale Molecular Dynamics Simulations
      Kostritskii, Andrei Yu.; Kondinskaia, Diana A.; Nesterenko, Alexey M.; Gurtovenko, Andrey A.
      Langmuir (2016), 32 (40), 10402-10414CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Although synthetic cationic polymers represent a promising class of effective antibacterial agents, the mol. mechanisms behind their antimicrobial activity remain poorly understood. To this end, we employ at.-scale mol. dynamics simulations to explore adsorption of several linear cationic polymers of different chem. structure and protonation (polyallylamine (PAA), polyethylenimine (PEI), polyvinylamine (PVA) and poly-L-lysine (PLL)) on model bacterial membranes (4:1 mixt. of zwitterionic phosphatidylethanolamine (PE) and anionic phosphatidylglycerol (PG) lipids). Overall, our findings show that binding of polycations to the anionic membrane surface effectively neutralizes its charge, leading to the reorientation of water mols. close to the lipid/water interface and to the partial release of counterions to the water phase. In certain cases one has even an overcharging of the membrane, which was shown to be a cooperative effect of polymer charges and lipid counterions. Protonated amine groups of polycations are found to interact preferably with head groups of anionic lipids, giving rise to formation of hydrogen bonds and to a noticeable lateral immobilization of the lipids. While all the above findings are mostly defined by the overall charge of a polymer, we found that the polymer architecture also matters. In particular, PVA and PEI are able to accumulate anionic PG lipids on the membrane surface, leading to lipid segregation. In turn, PLL whose charge twice exceeds charges of PVA/PEI does not induce such lipid segregation due to its considerably less compact architecture and relatively long side chains. We also show that partitioning of a polycation into the lipid/water interface is an interplay between its protonation level (the overall charge) and hydrophobicity of the backbone. Therefore, a possible strategy in creating highly efficient antimicrobial polymeric agents could be in tuning these polycation's properties through proper combination of protonated and hydrophobic blocks.
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    74. 74
      Kondinskaia, D. A.; Gurtovenko, A. A. Supramolecular complexes of DNA with cationic polymers: The effect of polymer concentration. Polymer 2018, 142, 277– 284,  DOI: 10.1016/j.polymer.2018.03.048
      74
      Supramolecular complexes of DNA with cationic polymers: The effect of polymer concentration
      Kondinskaia, Diana A.; Gurtovenko, Andrey A.
      Polymer (2018), 142 (), 277-284CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
      Supramol. complexes of DNA with cationic polymers are of tremendous importance as these polymers can successfully be used in gene therapy as delivery vectors of genetic material. In this work we employ atomistic mol. dynamics simulations to get an insight into the impact of polymer concn. on the structural and electrostatic properties of the complexes of DNA and cationic polymers. Four linear cationic polymers of different chem. structure and protonation state were studied: polyethylenimine (PEI), poly-L-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). For all considered polymers our computational findings clearly demonstrate that increasing the polymer concn. leads to the overcharging of the DNA mol. This is relevant as the overall pos. charge of the DNA-polycation complex is considered to be a prerequisite for efficient binding of the polyplexes to neg. charged cell membranes. However, the concn. effects themselves are found to be sensitive to the chem. structure of a polymer. In particular, flexible PEI chains, being characterized by the high affinity to DNA's phosphate groups, are able to bind to DNA in an independent manner. As a result, DNA and PEIs form compact complexes with the largest cumulative pos. charge among all four types of cationic polymers under study. In contrast, PVA chains show the affinity to the major groove of DNA due to the hydrophobic nature of their backbones. This leads to stronger interactions with the DNA mols. and to the competition between PVA chains for DNA binding sites. This competition is responsible for the obsd. satn. in the PVA-induced neutralizing of the DNA charges when the PVA concn. increases. As for PLL and PAA, both these polycations are found to be less effective in neutralizing the charge of the polyanionic DNA mols. as compared to PEI and PVA. PLL has relatively long side chains, so that some of them cannot access DNA phosphates and reside in aq. soln. In turn, PAA has a low protonation level, leading to a weak electrostatic binding to DNA. Overall, our findings can relate the properties of supramol. DNA-polycation complexes at elevated polymer concns. with the chem. structure of a polycation and therefore can be useful for the development of novel, highly efficient polycation-based delivery vectors of DNA.
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    75. 75
      Rohs, R.; West, S. M.; Sosinsky, A.; Liu, P.; Mann, R. S.; Honig, B. The role of DNA shape in protein-DNA recognition. Nature 2009, 461, 1248– 1253,  DOI: 10.1038/nature08473
      75
      The role of DNA shape in protein-DNA recognition
      Rohs, Remo; West, Sean M.; Sosinsky, Alona; Liu, Peng; Mann, Richard S.; Honig, Barry
      Nature (London, United Kingdom) (2009), 461 (7268), 1248-1253CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The recognition of specific DNA sequences by proteins is thought to depend on 2 types of mechanism: one that involves the formation of H-bonds with specific bases, primarily in the major groove, and one involving sequence-dependent deformations of the DNA helix. Here, by comprehensively analyzing the 3-dimensional structures of protein-DNA complexes, the authors show that the binding of Arg residues to narrow minor grooves is a widely used mode for protein-DNA recognition. This readout mechanism exploits the phenomenon that narrow minor grooves strongly enhance the neg. electrostatic potential of the DNA. The nucleosome core particle offers a prominent example of this effect. Minor-groove narrowing is often assocd. with the presence of A-tracts, AT-rich sequences that exclude the flexible TpA step. These findings indicate that the ability to detect local variations in DNA shape and electrostatic potential is a general mechanism that enables proteins to use information in the minor groove, which otherwise offers few opportunities for the formation of base-specific H-bonds, to achieve DNA-binding specificity.
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    76. 76
      Andrews, A. J.; Luger, K. Nucleosome structure(s) and stability: variations on a theme. Annu. Rev. Biophys. 2011, 40, 99– 117,  DOI: 10.1146/annurev-biophys-042910-155329
      76
      Nucleosome structure(s) and stability: variations on a theme
      Andrews, Andrew J.; Luger, Karolin
      Annual Review of Biophysics (2011), 40 (), 99-117CODEN: ARBNCV; ISSN:1936-122X. (Annual Reviews Inc.)
      A review. Chromatin is a highly regulated, modular nucleoprotein complex that is central to many processes in eukaryotes. The organization of DNA into nucleosomes and higher-order structures has profound implications for DNA accessibility. Alternative structural states of the nucleosome, and the thermodn. parameters governing its assembly and disassembly, need to be considered in order to understand how access to nucleosomal DNA is regulated. Here, the authors provide a brief historical account of how the overriding perception regarding aspects of nucleosome structure has changed over the past 30 yr. The authors discuss recent tech. advances regarding nucleosome structure and its phys. characterization and review the evidence for alternative nucleosome conformations and their implications for nucleosome and chromatin dynamics.
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    77. 77
      Hub, J. S.; de Groot, B. L. Detection of functional modes in protein dynamics. PLoS Comput. Biol. 2009, 5, e1000480,  DOI: 10.1371/journal.pcbi.1000480
      77
      Detection of functional modes in protein dynamics
      Hub Jochen S; de Groot Bert L
      PLoS computational biology (2009), 5 (8), e1000480 ISSN:.
      Proteins frequently accomplish their biological function by collective atomic motions. Yet the identification of collective motions related to a specific protein function from, e.g., a molecular dynamics trajectory is often non-trivial. Here, we propose a novel technique termed "functional mode analysis" that aims to detect the collective motion that is directly related to a particular protein function. Based on an ensemble of structures, together with an arbitrary "functional quantity" that quantifies the functional state of the protein, the technique detects the collective motion that is maximally correlated to the functional quantity. The functional quantity could, e.g., correspond to a geometric, electrostatic, or chemical observable, or any other variable that is relevant to the function of the protein. In addition, the motion that displays the largest likelihood to induce a substantial change in the functional quantity is estimated from the given protein ensemble. Two different correlation measures are applied: first, the Pearson correlation coefficient that measures linear correlation only; and second, the mutual information that can assess any kind of interdependence. Detecting the maximally correlated motion allows one to derive a model for the functional state in terms of a single collective coordinate. The new approach is illustrated using a number of biomolecules, including a polyalanine-helix, T4 lysozyme, Trp-cage, and leucine-binding protein.
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    78. 78
      Krivobokova, T.; Briones, R.; Hub, J. S.; Munk, A.; de Groot, B. L. Partial least-squares functional mode analysis: application to the membrane proteins AQP1, Aqy1, and CLC-ec1. Biophys. J. 2012, 103, 786– 796,  DOI: 10.1016/j.bpj.2012.07.022
      78
      Partial Least-Squares Functional Mode Analysis: Application to the Membrane Proteins AQP1, Aqy1, and CLC-ec1
      Krivobokova, Tatyana; Briones, Rodolfo; Hub, Jochen S.; Munk, Axel; de Groot, Bert L.
      Biophysical Journal (2012), 103 (4), 786-796CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      We introduce an approach based on the recently introduced functional mode anal. to identify collective modes of internal dynamics that maximally correlate to an external order parameter of functional interest. Input structural data can be either exptl. detd. structure ensembles or simulated ensembles, such as mol. dynamics trajectories. Partial least-squares regression is shown to yield a robust soln. to the multidimensional optimization problem, with a minimal and controllable risk of overfitting, as shown by extensive cross-validation. Several examples illustrate that the partial least-squares-based functional mode anal. successfully reveals the collective dynamics underlying the fluctuations in selected functional order parameters. Applications to T4 lysozyme, the Trp-cage, the aquaporin channels Aqy1 and hAQP1, and the CLC-ec1 chloride antiporter are presented in which the active site geometry, the hydrophobic solvent-accessible surface, channel gating dynamics, water permeability (pf), and a dihedral angle are defined as functional order parameters. The Aqy1 case reveals a gating mechanism that connects the inner channel gating residues with the protein surface, thereby providing an explanation of how the membrane may affect the channel. hAQP1 shows how the pf correlates with structural changes around the arom./arginine region of the pore. The CLC-ec1 application shows how local motions of the gating Glu148 couple to a collective motion that affects ion affinity in the pore.
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    79. 79
      Bratanov, D.; Kovalev, K.; Machtens, J.-P.; Astashkin, R.; Chizhov, I.; Soloviov, D.; Volkov, D.; Polovinkin, V.; Zabelskii, D.; Mager, T.; Gushchin, I.; Rokitskaya, T.; Antonenko, Y.; Alekseev, A.; Shevchenko, V.; Yutin, N.; Rosselli, R.; Baeken, C.; Borshchevskiy, V.; Bourenkov, G.; Popov, A.; Balandin, T.; Büldt, G.; Manstein, D. J.; Rodriguez-Valera, F.; Fahlke, C.; Bamberg, E.; Koonin, E.; Gordeliy, V. Unique structure and function of viral rhodopsins. Nat. Commun. 2019, 10, 4939  DOI: 10.1038/s41467-019-12718-0
      79
      Unique structure and function of viral rhodopsins
      Bratanov Dmitry; Kovalev Kirill; Volkov Dmytro; Polovinkin Vitaly; Zabelskii Dmitrii; Alekseev Alexey; Shevchenko Vitaly; Baeken Christian; Borshchevskiy Valentin; Balandin Taras; Gordeliy Valentin; Bratanov Dmitry; Kovalev Kirill; Volkov Dmytro; Zabelskii Dmitrii; Alekseev Alexey; Shevchenko Vitaly; Baeken Christian; Borshchevskiy Valentin; Balandin Taras; Gordeliy Valentin; Bratanov Dmitry; Kovalev Kirill; Astashkin Roman; Polovinkin Vitaly; Gordeliy Valentin; Kovalev Kirill; Astashkin Roman; Soloviov Dmytro; Volkov Dmytro; Zabelskii Dmitrii; Gushchin Ivan; Alekseev Alexey; Shevchenko Vitaly; Borshchevskiy Valentin; Buldt Georg; Fahlke Christoph; Bamberg Ernst; Gordeliy Valentin; Kovalev Kirill; Alekseev Alexey; Shevchenko Vitaly; Kovalev Kirill; Machtens Jan-Philipp; Fahlke Christoph; Machtens Jan-Philipp; Chizhov Igor; Manstein Dietmar J; Soloviov Dmytro; Soloviov Dmytro; Soloviov Dmytro; Mager Thomas; Bamberg Ernst; Rokitskaya Tatyana; Antonenko Yuri; Yutin Natalya; Koonin Eugene; Rosselli Riccardo; Rodriguez-Valera Francisco; Bourenkov Gleb; Popov Alexander
      Nature communications (2019), 10 (1), 4939 ISSN:.
      Recently, two groups of rhodopsin genes were identified in large double-stranded DNA viruses. The structure and function of viral rhodopsins are unknown. We present functional characterization and high-resolution structure of an Organic Lake Phycodnavirus rhodopsin II (OLPVRII) of group 2. It forms a pentamer, with a symmetrical, bottle-like central channel with the narrow vestibule in the cytoplasmic part covered by a ring of 5 arginines, whereas 5 phenylalanines form a hydrophobic barrier in its exit. The proton donor E42 is placed in the helix B. The structure is unique among the known rhodopsins. Structural and functional data and molecular dynamics suggest that OLPVRII might be a light-gated pentameric ion channel analogous to pentameric ligand-gated ion channels, however, future patch clamp experiments should prove this directly. The data shed light on a fundamentally distinct branch of rhodopsins and may contribute to the understanding of virus-host interactions in ecologically important marine protists.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jctc.0c01246.

    • Dependence of the short-range part of the potential on β; convergence of P2X3 profiles calculated from the raw SPME potential; time convergence of the g_elpot calculations; raw data on the electrostatic potential and Na1 occupancy in the GltPh simulations; chemical structure of PVA and PAA; groove-specific division of space in DNA systems; and simulation times for DNA and GltPh systems (PDF)


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