Evaluating Polarizable Biomembrane Simulations against Experiments

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This article references 130 other publications.

1. 1

   Gupta, C.; Sarkar, D.; Tieleman, D. P.; Singharoy, A. The ugly, bad, and good stories of large-scale biomolecular simulations. Curr. Opin. Struct. Biol. 2022, 73, 102338,  DOI: 10.1016/j.sbi.2022.102338

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   1

   The ugly, bad, and good stories of large-scale biomolecular simulations

   Gupta, Chitrak; Sarkar, Daipayan; Tieleman, D. Peter; Singharoy, Abhishek

   Current Opinion in Structural Biology (2022), 73 (), 102338CODEN: COSBEF; ISSN:0959-440X. (Elsevier Ltd.)

   Mol. modeling of large biomol. assemblies exemplifies a disruptive area holding both promises and contentions. Propelled by peta and exascale computing, several simulation methodologies have now matured into user-friendly tools that are successfully employed for modeling viruses, membranous nano-constructs, and key pieces of the genetic machinery. We present three unifying biophys. themes that emanate from some of the most recent multi-million atom simulation endeavors. Despite connecting mol. changes with phenotypic outcomes, the quality measures of these simulations remain questionable. We discuss the existing and upcoming strategies for constructing representative ensembles of large systems, how new computing technologies will boost this area, and make a point that integrative modeling guided by exptl. data is the future of biomol. computations.
2. 2

   Inakollu, V. S.; Geerke, D. P.; Rowley, C. N.; Yu, H. Polarisable force fields: what do they add in biomolecular simulations?. Curr. Opin. Struct. Biol. 2020, 61, 182– 190,  DOI: 10.1016/j.sbi.2019.12.012

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   Polarisable force fields: what do they add in biomolecular simulations

   Inakollu, V. S. Sandeep; Geerke, Daan P.; Rowley, Christopher N.; Yu, Haibo

   Current Opinion in Structural Biology (2020), 61 (), 182-190CODEN: COSBEF; ISSN:0959-440X. (Elsevier Ltd.)

   A review. The quality of biomol. simulations critically depends on the accuracy of the force field used to calc. the potential energy of the mol. configurations. Currently, most simulations employ non-polarisable force fields, which describe electrostatic interactions as the sum of Coulombic interactions between fixed at. charges. Polarisation of these charge distributions is incorporated only in a mean-field manner. In the past decade, extensive efforts have been devoted to developing simple, efficient, and yet generally applicable polarisable force fields for biomol. simulations. In this review, we summarise the latest developments in accounting for key biomol. interactions with polarisable force fields and applications to address challenging biol. questions. In the end, we provide an outlook for future development in polarisable force fields.
3. 3

   Fried, S. D.; Wang, L.-P.; Boxer, S. G.; Ren, P.; Pande, V. S. Calculations of the Electric Fields in Liquid Solutions. J. Phys. Chem. B 2013, 117, 16236– 16248,  DOI: 10.1021/jp410720y

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   Calculations of the Electric Fields in Liquid Solutions

   Fried, Stephen D.; Wang, Lee-Ping; Boxer, Steven G.; Ren, Pengyu; Pande, Vijay S.

   Journal of Physical Chemistry B (2013), 117 (50), 16236-16248CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

   The elec. field created by a condensed-phase environment is a powerful and convenient descriptor for intermol. interactions. Not only does it provide a unifying language to compare many different types of interactions, but it also possesses clear connections to exptl. observables, such as vibrational Stark effects. We calc. here the elec. fields experienced by a vibrational chromophore (the carbonyl group of acetophenone) in an array of solvents of diverse polarities using mol. dynamics simulations with the AMOEBA polarizable force field. The mean and variance of the calcd. elec. fields correlate well with solvent-induced frequency shifts and band broadening, suggesting Stark effects as the underlying mechanism of these key soln.-phase spectral effects. Compared to fixed-charge and continuum models, AMOEBA was the only model examd. that could describe nonpolar, polar, and hydrogen bonding environments in a consistent fashion. Nevertheless, we found that fixed-charge force fields and continuum models were able to replicate some results of the polarizable simulations accurately, allowing us to clearly identify which properties and situations require explicit polarization and/or atomistic representations to be modeled properly, and to identify for which properties and situations simpler models are sufficient. We also discuss the ramifications of these results for modeling electrostatics in complex environments, such as proteins.
4. 4

   Kozuch, J.; Schneider, S. H.; Zheng, C.; Ji, Z.; Bradshaw, R. T.; Boxer, S. G. Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case. J. Phys. Chem. B 2021, 125, 4415– 4427,  DOI: 10.1021/acs.jpcb.1c00578

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   Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

   Kozuch, Jacek; Schneider, Samuel H.; Zheng, Chu; Ji, Zhe; Bradshaw, Richard T.; Boxer, Steven G.

   Journal of Physical Chemistry B (2021), 125 (17), 4415-4427CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

   Noncovalent interactions underlie nearly all mol. processes in the condensed phase from solvation to catalysis. Their quantification within a phys. consistent framework remains challenging. Exptl. vibrational Stark effect (VSE)-based solvatochromism can be combined with mol. dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid mols. and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach toward more complex (bio)mols., such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based elec. fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the elec. fields are correlated to conformation-dependent effects of the flexible PenG side chain, including both the local solvation structure and solute conformational sampling in MD. Addnl., we identified that MD-based elec. fields are consistently overestimated in three-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for expt.-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)mols.
5. 5

   Nochebuena, J.; Piquemal, J.-P.; Liu, S.; Cisneros, G. A. Cooperativity and Frustration Effects (or Lack Thereof) in Polarizable and Non-polarizable Force Fields. J. Chem. Theory Comput. 2023, 19, 7715,  DOI: 10.1021/acs.jctc.3c00762

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   Roux, B.; Bernèche, S.; Egwolf, B.; Lev, B.; Noskov, S. Y.; Rowley, C. N.; Yu, H. Ion selectivity in channels and transporters. J. Gen. Physiol. 2011, 137, 415– 426,  DOI: 10.1085/jgp.201010577

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   Ion selectivity in channels and transporters

   Roux, Benoit; Berneche, Simon; Egwolf, Bernhard; Lev, Bogdan; Noskov, Sergei Y.; Rowley, Christopher N.; Yu, Haibo

   Journal of General Physiology (2011), 137 (5), 415-426CODEN: JGPLAD; ISSN:0022-1295. (Rockefeller University Press)

   A review presents the understanding of ion selectivity as it has evolved over about 15 years from studies based on various specific structures: gramicidin A channels, the KcsA channel, the NaK channel, the LeuT transporter, and the Na/K pump. It also discusses the insights that can be gained from simple models, which can be used to illustrate and clarify fundamental phys. principles governing ion selectivity in channels and transporters.
7. 7

   Klesse, G.; Rao, S.; Tucker, S. J.; Sansom, M. S. Induced polarization in molecular dynamics simulations of the 5-HT3 receptor channel. J. Am. Chem. Soc. 2020, 142, 9415– 9427,  DOI: 10.1021/jacs.0c02394

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   Induced Polarization in Molecular Dynamics Simulations of the 5-HT3 Receptor Channel

   Klesse, Gianni; Rao, Shanlin; Tucker, Stephen J.; Sansom, Mark S. P.

   Journal of the American Chemical Society (2020), 142 (20), 9415-9427CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   Ion channel proteins form water-filled nanoscale pores within lipid bilayers, and their properties are dependent on the complex behavior of water in a nanoconfined environment. Using a simplified model of the pore of the 5-HT3 receptor (5HT3R) which restrains the backbone structure to that of the parent channel protein from which it is derived, we compare additive with polarizable models in describing the behavior of water in nanopores. Mol. dynamics simulations were performed with four conformations of the channel: two closed state structures, an intermediate state, and an open state, each embedded in a phosphatidylcholine bilayer. Water d. profiles revealed that for all water models, the closed and intermediate states exhibited strong dewetting within the central hydrophobic gate region of the pore. However, the open state conformation exhibited varying degrees of hydration, ranging from partial wetting for the TIP4P/2005 water model to complete wetting for the polarizable AMOEBA14 model. Water dipole moments calcd. using polarizable force fields also revealed that water mols. remaining within dewetted sections of the pore resemble gas phase water. Free energy profiles for Na+ and for Cl- ions within the open state pore revealed more rugged energy landscapes using polarizable force fields, and the hydration no. profiles of these ions were also sensitive to induced polarization resulting in a substantive redn. of the no. of waters within the first hydration shell of Cl- while it permeates the pore. These results demonstrate that induced polarization can influence the complex behavior of water and ions within nanoscale pores and provides important new insights into their chem. properties.
8. 8

   Prajapati, J. D.; Mele, C.; Aksoyoglu, M. A.; Winterhalter, M.; Kleinekathöfer, U. Computational modeling of ion transport in bulk and through a nanopore using the drude polarizable force field. J. Chem. Inf. Model. 2020, 60, 3188– 3203,  DOI: 10.1021/acs.jcim.0c00389

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   Computational Modeling of Ion Transport in Bulk and through a Nanopore Using the Drude Polarizable Force Field

   Prajapati, Jigneshkumar Dahyabhai; Mele, Crystal; Aksoyoglu, Mehmet Alphan; Winterhalter, Mathias; Kleinekathoefer, Ulrich

   Journal of Chemical Information and Modeling (2020), 60 (6), 3188-3203CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

   In the past two decades, mol. dynamics simulations have become the method of choice for elucidating the transport mechanisms of ions through various membrane channels. Often, these simulations heavily rely on classical nonpolarizable force fields (FFs), which lack electronic polarizability in the treatment of the electrostatics. The recent advancements in the Drude polarizable FF lead to a complete set of parameters for water, ions, protein, and lipids, allowing for a more realistic modeling of membrane proteins. However, the quality of these Drude FFs remains untested for such systems. Here, we examine the quality of this FF set in two ways, i.e., (i) in simple ionic aq. soln. simulations and (ii) in more complex membrane channel simulations. First, the aq. solns. of KCl, NaCl, MgCl2, and CaCl2 salts are simulated using the polarizable Drude and the nonpolarizable CHARMM36 FFs. The bulk cond. has been estd. for both FF sets using applied-field simulations for several concns. and temps. in the case of all investigated salts and compared to exptl. findings. An excellent improvement in the ability of the Drude FF to reproduce the exptl. bulk conductivities for KCl, NaCl, and MgCl2 solns. can be obsd. but not in the case of CaCl2. Moreover, the outer membrane channel OmpC from the bacterium Escherichia coli has been employed to examine the ability of the polarizable and nonpolarizable FFs to reproduce ion transport-related quantities known from expt. Unbiased and applied-field simulations have been performed in the presence of KCl using both FF sets. Unlike for the bulk systems of aq. salt solns., it has been found that the Drude FF is not accurate in modeling KCl transport properties across the OmpC porin.
9. 9

   Yue, Z.; Wang, Z.; Voth, G. A. Ion permeation, selectivity, and electronic polarization in fluoride channels. Biophys. J. 2022, 121, 1336– 1347,  DOI: 10.1016/j.bpj.2022.02.019

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   Ion permeation, selectivity, and electronic polarization in fluoride channels

   Yue, Zhi; Wang, Zhi; Voth, Gregory A.

   Biophysical Journal (2022), 121 (7), 1336-1347CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

   Fluoride channels (Flucs) export toxic F- from the cytoplasm. Crystallog. and mutagenesis have identified several conserved residues crucial for fluoride transport, but the permeation mechanism at the mol. level has remained elusive. Herein, we have applied const.-pH mol. dynamics and free-energy-sampling methods to investigate fluoride permeation through a Fluc protein from Escherichia coli. We find that fluoride is facile to permeate in its charged form, i.e., F-, by traversing through a non-bonded network. The extraordinary F- selectivity is gained by the hydrogen-bonding capability of the central binding site and the Coulombic filter at the channel entrance. The F- permeation rate calcd. using an electronically polarizable force field is significantly more accurate compared with the exptl. value than that calcd. using a more std. additive force field, suggesting an essential role for electronic polarization in the F--Fluc interactions.
10. 10

    Salsbury, A. M.; Michel, H. M.; Lemkul, J. A. Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes. ACS Omega 2022, 7, 23368– 23379,  DOI: 10.1021/acsomega.2c01600

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    Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes

    Salsbury, Alexa M.; Michel, Haley M.; Lemkul, Justin A.

    ACS Omega (2022), 7 (27), 23368-23379CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)

    Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme-GQ interactions and dynamics important for potential drug design. GQs have a characteristic tetrad core, which is connected by loop regions. Within this architecture is G-hairpins, fold-back motifs that are thought to represent the first intermediate in GQ folding. To better understand the relation between G-hairpin motifs and GQs, the authors performed polarizable simulations of a two-tetrad telomeric GQ and an isolated SC11 telomeric G-hairpin. The telomeric GQ contains a G-triad, which functions as part of the tetrad core or linker regions, depending on the local conformational change. This triad and another motif below the tetrad core frequently bound ions and may represent druggable sites. Further, the authors obsd. the unbiased formation of a G-triad and a G-tetrad in simulations of the SC11 G-hairpin and found that cations can be partially hydrated while facilitating the formation of these motifs. Finally, K+ ions form specific interactions with guanine bases, while Na+ ions interact nonspecifically with bases in the structure. Together, these simulations provide new insights into the influence of ions on GQs, G-hairpins, and G-triad motifs.
11. 11

    Thole, B. Molecular polarizabilities calculated with a modified dipole interaction. Chem. Phys. 1981, 59, 341– 350,  DOI: 10.1016/0301-0104(81)85176-2

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    Molecular polarizabilities calculated with a modified dipole interaction

    Thole, B. T.

    Chemical Physics (1981), 59 (3), 341-50CODEN: CMPHC2; ISSN:0301-0104.

    The point dipole interaction model for mol. polarizability recently proposed by J. Applequist, et al., (1972) is modified by replacing the point dipole interaction by an interaction between smeared out dipoles. Rules are developed to indicate plausible forms for this modified interaction. The polarizabilities of a wide range of chem. different mols. can be calcd., using for each atom one polarizability independent of its chem. environment. The errors are comparable to exptl. uncertainty. Special care is taken to produce a model that tends to avoid infinite polarizabilities without use of cutoffs at short distances.
12. 12

    Ando, K. A stable fluctuating-charge polarizable model for molecular dynamics simulations: Application to aqueous electron transfers. J. Chem. Phys. 2001, 115, 5228– 5237,  DOI: 10.1063/1.1394923

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    A stable fluctuating-charge polarizable model for molecular dynamics simulations: Application to aqueous electron transfers

    Ando, Koji

    Journal of Chemical Physics (2001), 115 (11), 5228-5237CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    A stable and efficient variant of the dynamical fluctuating charge (fluc-q) model for electronically polarizable mol. dynamics (MD) simulation is developed and applied to electron transfer (ET) reactions in water. The energy divergence problem often encountered with the original form of the fluc-q model is essentially removed by introducing an alternative functional form for the electronic self-energy term of hydrogen atoms without any addnl. parameters. In the application to the aq. ET problem we find the following: For the present donor-acceptor (DA) model of moderate size, the induced dipole is slightly smaller in the first solvation shell than in the outer region even under the electrostatic field from the ion pair state of the DA, which suggests that the induced dipole is enhanced more in the solvent-solvent hydrogen-bonding structure. The structural aspects are also examd. via radial distribution functions. The solvent reorganization energy is demonstrated to be renormalized, both in the magnitude and in the slope along the inverse DA distance, due to coupling with electronic polarization. In the time correlation and spectral d. functions of the solvent reaction coordinate, the frequency of the librational coupling motion is slightly blue-shifted and its intensity is suppressed due to inclusion of the solvent electronic polarization. The impact of the electronic polarization on the scaled quantum energy gap law of the ET rate is found to be modest.
13. 13

    Grossfield, A.; Ren, P.; Ponder, J. W. Ion Solvation Thermodynamics from Simulation with a Polarizable Force Field. J. Am. Chem. Soc. 2003, 125, 15671– 15682,  DOI: 10.1021/ja037005r

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    Ion Solvation Thermodynamics from Simulation with a Polarizable Force Field

    Grossfield, Alan; Ren, Pengyu; Ponder, Jay W.

    Journal of the American Chemical Society (2003), 125 (50), 15671-15682CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Thermodn. measurements of the solvation of salts and electrolytes are relatively straightforward, but it is not possible to sep. total solvation free energies into distinct cation and anion contributions without ref. to an addnl. extra-thermodn. assumption. The present work attempts to resolve this difficulty using mol. dynamics simulations with the AMOEBA polarizable force field and perturbation techniques to directly compute abs. solvation free energies for potassium, sodium, and chloride ions in liq. water and formamide. Corresponding calcns. are also performed with two widely used nonpolarizable force fields. The simulations with the polarizable force field accurately reproduce in vacuo quantum mech. results, exptl. ion-cluster solvation enthalpies, and exptl. solvation free energies for whole salts, while the other force fields do not. The results indicate that calcns. with a polarizable force field can capture the thermodn. of ion solvation and that the solvation free energies of the individual ions differ by several kilocalories from commonly cited values.
14. 14

    Lamoureux, G.; Roux, B. Modeling induced polarization with classical Drude oscillators: Theory and molecular dynamics simulation algorithm. J. Chem. Phys. 2003, 119, 3025– 3039,  DOI: 10.1063/1.1589749

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    Modeling induced polarization with classical Drude oscillators: theory and molecular dynamics simulation algorithm

    Lamoureux, Guillaume; Roux, Benoit

    Journal of Chemical Physics (2003), 119 (6), 3025-3039CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    A simple treatment for incorporating induced polarization in computer simulations is formulated on the basis of the classical Drude oscillator model. In this model, electronic induction is represented by the displacement of a charge-carrying massless particle attached to a polarizable atom under the influence of the local elec. field. The traditional SCF regime of induced polarization is reproduced if these auxiliary particles are allowed to relax instantaneously to their local energy min. for any given fixed configuration of the atoms in the system. In practice, such treatment is computationally prohibitive for generating mol. dynamics trajectories because the elec. field must be recalcd. several times iteratively to satisfy the SCF condition, and it is important to seek a more efficient way to simulate the classical Drude oscillator model. It is demonstrated that a close approxn. to the SCF regime can be simulated efficiently by considering the dynamics of an extended Lagrangian in which a small mass is attributed to the auxiliary particles, and the amplitude of their oscillations away from the local energy min. is controlled with a low-temp. thermostat. A simulation algorithm in this modified two-temp. isobaric-isothermal ensemble is developed. The algorithm is tested and illustrated using a rigid three-site water model with one addnl. Drude particle attached to the oxygen which is closely related to the polarizable SPC model of Ahlstrom et al. [Mol. Phys. 68, 563 (1989)]. The tests with the extended Lagrangian show that stable and accurate mol. dynamics trajectories for large integration time steps (1 or 2 fs) can be generated and that liq. properties equiv. to SCF mol. dynamics can be reproduced at a fraction of the computational cost.
15. 15

    Antila, H. S.; Salonen, E. In Biomolecular Simulations: Methods and Protocols; Monticelli, L., Salonen, E., Eds.; Humana Press: Totowa, NJ, 2013; pp 215– 241.

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    Lemkul, J. A.; Huang, J.; Roux, B.; MacKerell, A. D. J. An Empirical Polarizable Force Field Based on the Classical Drude Oscillator Model: Development History and Recent Applications. Chem. Rev. 2016, 116, 4983– 5013,  DOI: 10.1021/acs.chemrev.5b00505

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    An Empirical Polarizable Force Field Based on the Classical Drude Oscillator Model: Development History and Recent Applications

    Lemkul, Justin A.; Huang, Jing; Roux, Benoit; MacKerell, Alexander D., Jr.

    Chemical Reviews (Washington, DC, United States) (2016), 116 (9), 4983-5013CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

    A review. Mol. mechanics force fields that explicitly account for induced polarization represent the next generation of phys. models for mol. dynamics simulations. Several methods exist for modeling induced polarization, and here we review the classical Drude oscillator model, in which electronic degrees of freedom are modeled by charged particles attached to the nuclei of their core atoms by harmonic springs. We describe the latest developments in Drude force field parametrization and application, primarily in the last 15 years. Emphasis is placed on the Drude-2013 polarizable force field for proteins, DNA, lipids, and carbohydrates. We discuss its parametrization protocol, development history, and recent simulations of biol. interesting systems, highlighting specific studies in which induced polarization plays a crit. role in reproducing exptl. observables and understanding phys. behavior. As the Drude oscillator model is computationally tractable and available in a wide range of simulation packages, it is anticipated that use of these more complex phys. models will lead to new and important discoveries of the phys. forces driving a range of chem. and biol. phenomena.
17. 17

    Baker, C. M. Polarizable force fields for molecular dynamics simulations of biomolecules. Wiley Interdisciplinary Reviews: Computational Molecular Science 2015, 5, 241– 254,  DOI: 10.1002/wcms.1215

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    Polarizable force fields for molecular dynamics simulations of biomolecules

    Baker, Christopher M.

    Wiley Interdisciplinary Reviews: Computational Molecular Science (2015), 5 (2), 241-254CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)

    Mol. dynamics simulations are well established for the study of biomol. systems. Within these simulations, energy functions known as force fields are used to det. the forces acting on atoms and mols. While these force fields have been very successful, they contain a no. of approxns., included to overcome limitations in computing power. One of the most important of these approxns. is the omission of polarizability, the process by which the charge distribution in a mol. changes in response to its environment. Since polarizability is known to be important in many biochem. situations, and since advances in computer hardware have reduced the need for approxns. within force fields, there is major interest in the use of force fields that include an explicit representation of polarizability. As such, a no. of polarizable force fields have been under development: these have been largely exptl., and their use restricted to specialized researchers. This situation is now changing. Parameters for fully optimized polarizable force fields are being published, and assocd. code incorporated into std. simulation software. Simulations on the hundred-nanosecond timescale are being reported, and are now within reach of all simulation scientists. In this overview, I examine the polarizable force fields available for the simulation of biomols., the systems to which they have been applied, and the benefits and challenges that polarizability can bring. In considering future directions for development of polarizable force fields, I examine lessons learnt from non-polarizable force fields, and highlight issues that remain to be addressed. WIREs Comput Mol Sci 2015, 5:241-254. doi: 10.1002/wcms.1215. Conflict of interest: The author has declared no conflicts of interest for this article.
18. 18

    Jing, Z.; Liu, C.; Cheng, S. Y.; Qi, R.; Walker, B. D.; Piquemal, J.-P.; Ren, P. Polarizable force fields for biomolecular simulations: Recent advances and applications. Annual Review of biophysics 2019, 48, 371,  DOI: 10.1146/annurev-biophys-070317-033349

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    Polarizable Force Fields for Biomolecular Simulations: Recent Advances and Applications

    Jing, Zhifeng; Liu, Chengwen; Cheng, Sara Y.; Qi, Rui; Walker, Brandon D.; Piquemal, Jean-Philip; Ren, Pengyu

    Annual Review of Biophysics (2019), 48 (), 371-394CODEN: ARBNCV; ISSN:1936-122X. (Annual Reviews)

    A review. Realistic modeling of biomol. systems requires an accurate treatment of electrostatics, including electronic polarization. Due to recent advances in phys. models, simulation algorithms, and computing hardware, biomol. simulations with advanced force fields at biol. relevant timescales are becoming increasingly promising. These advancements have not only led to new biophys. insights but also afforded opportunities to advance our understanding of fundamental intermol. forces. This article describes the recent advances and applications, as well as future directions, of polarizable force fields in biomol. simulations.
19. 19

    Li, H.; Chowdhary, J.; Huang, L.; He, X.; MacKerell, A. D., Jr; Roux, B. Drude polarizable force field for molecular dynamics simulations of saturated and unsaturated zwitterionic lipids. J. Chem. Theory Comput. 2017, 13, 4535– 4552,  DOI: 10.1021/acs.jctc.7b00262

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    Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids

    Li, Hui; Chowdhary, Janamejaya; Huang, Lei; He, Xibing; MacKerell, Alexander D.; Roux, Benoit

    Journal of Chemical Theory and Computation (2017), 13 (9), 4535-4552CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Additive force fields are designed to account for induced electronic polarization in a mean-field av. way, using effective empirical fixed charges. The limitation of this approxn. is cause for serious concerns, particularly in the case of lipid membranes, where the mol. environment undergoes dramatic variations over microscopic length scales. A polarizable force field based on the classical Drude oscillator offers a practical and computationally efficient framework for an improved representation of electrostatic interactions in mol. simulations. Building on the first-generation Drude polarizable force field for the dipalmitoylphosphatidylcholine 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) mol., the present effort was undertaken to improve this initial model and expand the force field to a wider range of phospholipid mols. New lipids parametrized include dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The iterative optimization protocol employed in this effort led to lipid models that achieve a good balance between reproducing quantum mech. data on model compd. representative of phospholipids and reproducing a range of exptl. condensed phase properties of bilayers. A parametrization strategy based on a restrained ensemble-max. entropy methodol. was used to help accurately match the exptl. NMR order parameters in the polar headgroup region. All the parameters were developed to be compatible with the remainder of the Drude polarizable force field, which includes water, ions, proteins, DNA, and selected carbohydrates.
20. 20

    Chu, H.; Peng, X.; Li, Y.; Zhang, Y.; Li, G. A polarizable atomic multipole-based force field for molecular dynamics simulations of anionic lipids. Molecules 2018, 23, 77,  DOI: 10.3390/molecules23010077

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    A polarizable atomic multipole-based force field for molecular dynamics simulations of anionic lipids

    Chu, Huiying; Peng, Xiangda; Li, Yan; Zhang, Yuebin; Li, Guohui

    Molecules (2018), 23 (1), 77/1-77/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)

    In all of the classical force fields, electrostatic interaction is simply treated and explicit electronic polarizability is neglected. The condensed-phase polarization, relative to the gas-phase charge distributions, is commonly accounted for in an av. way by increasing the at. charges, which remain fixed throughout simulations. Based on the lipid polarizable force field DMPC and following the same framework as Atomic Multipole Optimized Energetics for Biomol. (AMOEBA) simulation, the present effort expands the force field to new anionic lipid models, in which the new lipids contain DMPG and POPS. The parameters are compatible with the AMOEBA force field, which includes water, ions, proteins, etc. The charge distribution of each atom is represented by the permanent at. monopole, dipole and quadrupole moments, which are derived from the ab initio gas phase calcns. Many-body polarization including the inter- and intramol. polarization is modeled in a consistent manner with distributed at. polarizabilities. Mol. dynamics simulations of the two aq. DMPG and POPS membrane bilayer systems, consisting of 72 lipids with water mols., were then carried out to validate the force field parameters. Membrane width, area per lipid, vol. per lipid, deuterium order parameters, electron d. profile, electrostatic p.d. between the center of the bilayer and water are all calcd., and compared with limited exptl. data.
21. 21

    Lynch, C. I.; Klesse, G.; Rao, S.; Tucker, S. J.; Sansom, M. S. P. Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models. ACS Nano 2021, 15, 19098– 19108,  DOI: 10.1021/acsnano.1c06443

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    Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models

    Lynch, Charlotte I.; Klesse, Gianni; Rao, Shanlin; Tucker, Stephen J.; Sansom, Mark S. P.

    ACS Nano (2021), 15 (12), 19098-19108CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    Water mols. within biol. ion channels are in a nanoconfined environment and therefore exhibit behaviors which differ from that of bulk water. Here, the authors study the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously dewet to form a "vapor lock" if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore. Using mol. dynamics simulations with both rigid fixed-charge and polarizable (AMOEBA) force fields, the authors study this wetting/dewetting behavior in the TMEM175 ion channel. The authors examine how a range of rigid fixed-charge and polarizable water models affect wetting/dewetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, the rigid fixed-charge water models lead to similar wetting/dewetting behaviors, but the polarizable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for mol. simulations of nanoconfined water, as it implies that polarizability may need to be included if the authors are to gain detailed mechanistic insights into wetting/dewetting processes. These findings are of importance for the design of functionalized biomimetic nanopores (for e.g. sensing or desalination), as well as for furthering the authors' understanding of the mechanistic processes underlying biol. ion channel function.
22. 22

    Chen, P.; Vorobyov, I.; Roux, B.; Allen, T. W. Molecular Dynamics Simulations Based on Polarizable Models Show that Ion Permeation Interconverts between Different Mechanisms as a Function of Membrane Thickness. J. Phys. Chem. B 2021, 125, 1020– 1035,  DOI: 10.1021/acs.jpcb.0c08613

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    22

    Molecular Dynamics Simulations Based on Polarizable Models Show that Ion Permeation Interconverts between Different Mechanisms as a Function of Membrane Thickness

    Chen, Peiran; Vorobyov, Igor; Roux, Benoit; Allen, Toby W.

    Journal of Physical Chemistry B (2021), 125 (4), 1020-1035CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Different mechanisms have been proposed to explain the permeation of charged compds. through lipid membranes. Overall, it is expected that an ion-induced defect permeation mechanism, where substantial membrane deformations accompany ion movement, should be dominant in thin membranes but that a soly.-diffusion mechanism, where ions partition into the membrane core with large assocd. dehydration energy costs, becomes dominant in thicker membranes. However, while this phys. picture is intuitively reasonable, capturing the interconversion between these two permeation mechanisms in mol. dynamics (MD) simulations based on at. models is challenging. In particular, simulations relying on nonpolarizable force fields are artificially unfavorable to the soly.-diffusion mechanism, as induced polarization of the nonpolar hydrocarbon is ignored, causing overestimated free energy costs for charged mols. to enter into this region of the membrane. In this study, all-atom MD simulations based on nonpolarizable and polarizable force fields are used to quant. characterize the permeation process for the arginine side chain analog methyl-guanidinium through bilayer membranes of mono-unsatd. phosphatidylcholine lipids with and without cholesterol, resulting in thicknesses spanning from ∼24 to ∼42 Å. With simulations based on a nonpolarizable force field, ion translocation can take place solely through an ion-induced defect mechanism, with free energy barriers increasing linearly from 14 to 40 kcal/mol, depending on the thickness. However, with simulations based on a polarizable force field, ion translocation is predominantly dominated by an ion-induced defect mechanism in thin membranes, which progressively converts to a soly.-diffusion mechanism as the membranes get thicker. The transition between the two mechanisms occurs at a thickness of ∼29 Å, with lipid tails of 22 or more carbon atoms. This situation appears to represent the upper limit for ion-induced defect permeation within the current polarizable models. Beyond this thickness, it becomes energetically preferable for the ion to dehydrate and partition into the membrane core - a phenomenon that cannot be captured using the nonpolarizable models. Induced electronic polarizability therefore leads not just to a shift in permeation energetics but to an interconversion between two strikingly different phys. mechanisms. The result highlights the importance of induced polarizability in modeling lipid membranes.
23. 23

    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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    23

    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.
24. 24

    Melcr, J.; Ferreira, T. M.; Jungwirth, P.; Ollila, O. S. Improved Cation Binding to Lipid Bilayers with Negatively Charged POPS by Effective Inclusion of Electronic Polarization. J. Chem. Theory Comput. 2020, 16, 738,  DOI: 10.1021/acs.jctc.9b00824

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    24

    Improved Cation Binding to Lipid Bilayers with Negatively Charged POPS by Effective Inclusion of Electronic Polarization

    Melcr Josef; Jungwirth Pavel; Ollila O H Samuli; Melcr Josef; Ferreira Tiago M; Ollila O H Samuli

    Journal of chemical theory and computation (2020), 16 (1), 738-748 ISSN:.

    Phosphatidylserine (PS) lipids are important signaling molecules and the most common negatively charged lipids in eukaryotic membranes. The signaling can be often regulated by calcium, but its interactions with PS headgroups are not fully understood. Classical molecular dynamics (MD) simulations can potentially give detailed description of lipid-ion interactions, but the results strongly depend on the used force field. Here, we apply the electronic continuum correction (ECC) to the Amber Lipid17 parameters of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) lipid to improve its interactions with K(+), Na(+), and Ca(2+) ions. The partial charges of the headgroup, glycerol backbone, and carbonyls of POPS, bearing a unit negative charge, were scaled with a factor of 0.75, derived for monovalent ions, and the Lennard-Jones σ parameters of the same segments were scaled with a factor of 0.89. The resulting ECC-POPS model gives more realistic interactions with Na(+) and Ca(2+) cations than the original Amber Lipid17 parameters when validated using headgroup order parameters and the "electrometer concept". In ECC-lipids simulations, populations of complexes of Ca(2+) cations with more than two PS lipids are negligible, and interactions of Ca(2+) cations with only carboxylate groups are twice more likely than with only phosphate groups, while interactions with carbonyls almost entirely involve other groups as well. Our results pave the way for more realistic MD simulations of biomolecular systems with anionic membranes, allowing signaling processes involving PS and Ca(2+) to be elucidated.
25. 25

    Nencini, R.; Ollila, O. H. S. Charged Small Molecule Binding to Membranes in MD Simulations Evaluated against NMR Experiments. J. Phys. Chem. B 2022, 126, 6955– 6963,  DOI: 10.1021/acs.jpcb.2c05024

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    25

    Charged Small Molecule Binding to Membranes in MD Simulations Evaluated against NMR Experiments

    Nencini, Ricky; Ollila, O. H. Samuli

    Journal of Physical Chemistry B (2022), 126 (36), 6955-6963CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Interactions of charged mols. with biomembranes regulate many of their biol. activities, but their binding affinities to lipid bilayers are difficult to measure exptl. and model theor. Classical mol. dynamics (MD) simulations have the potential to capture the complex interactions detg. how charged biomols. interact with membranes, but systematic overbinding of sodium and calcium cations in std. MD simulations raises the question of how accurately force fields capture the interactions between lipid membranes and charged biomols. Here, we evaluate the binding of pos. charged small mols., etidocaine, and tetraphenylphosphonium to a phosphatidylcholine (POPC) lipid bilayer using the changes in lipid head-group order parameters. We obsd. that these mols. behave oppositely to calcium and sodium ions when binding to membranes: (i) their binding affinities are not overestimated by std. force field parameters, (ii) implicit inclusion of electronic polarizability increases their binding affinity, and (iii) they penetrate into the hydrophobic membrane core. Our results can be explained by distinct binding mechanisms of charged small mols. with hydrophobic moieties and monoat. ions. The binding of the former is driven by hydrophobic effects, while the latter has direct electrostatic interactions with lipids. In addn. to elucidating how different kinds of charged biomols. bind to membranes, we deliver tools for further development of MD simulation parameters and methodol.
26. 26

    Yu, Y.; Venable, R. M.; Thirman, J.; Chatterjee, P.; Kumar, A.; Pastor, R. W.; Roux, B.; MacKerell, A. D., Jr; Klauda, J. B. Drude Polarizable Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Saturated and Monounsaturated Zwitterionic Lipids. J. Chem. Theory Comput. 2023, 19, 2590– 2605,  DOI: 10.1021/acs.jctc.3c00203

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    26

    Drude Polarizable Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Saturated and Monounsaturated Zwitterionic Lipids

    Yu, Yalun; Venable, Richard M.; Thirman, Jonathan; Chatterjee, Payal; Kumar, Anmol; Pastor, Richard W.; Roux, Benoit; MacKerell Jr., Alexander D.; Klauda, Jeffery B.

    Journal of Chemical Theory and Computation (2023), 19 (9), 2590-2605CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Accurate empirical force fields of lipid mols. are a crit. component of mol. dynamics simulation studies aimed at investigating properties of monolayers, bilayers, micelles, vesicles, and liposomes, as well as heterogeneous systems, such as protein-membrane complexes, bacterial cell walls, and more. While the majority of lipid force field-based simulations have been performed using pairwise-additive nonpolarizable models, advances have been made in the development of the polarizable force field based on the classical Drude oscillator model. In the present study, we undertake further optimization of the Drude lipid force field, termed Drude2023, including improved treatment of the phosphate and glycerol linker region of PC and PE headgroups, addnl. optimization of the alkene group in monounsatd. lipids, and inclusion of long-range Lennard-Jones interactions using the particle-mesh Ewald method. Initial optimization targeted quantum mech. (QM) data on small model compds. representative of the linker region. Subsequent optimization targeted QM data on larger model compds., exptl. data, and dihedral potentials of mean force from the CHARMM36 additive lipid force field using a parameter reweighting protocol. The use of both exptl. and QM target data during the reweighting protocol is shown to produce phys. reasonable parameters that reproduce a collection of exptl. observables. Target data for optimization included surface area/lipid for DPPC, DSPC, DMPC, and DLPC bilayers and NMR (NMR) order parameters for DPPC bilayers. Validation data include prediction of membrane thickness, scattering form factors, electrostatic potential profiles, compressibility moduli, surface area per lipid, water permeability, NMR T1 relaxation times, diffusion consts., and monolayer surface tensions for a variety of satd. and unsatd. lipid mono- and bilayers. Overall, the agreement with exptl. data is quite good, though the results are less satisfactory for the NMR T1 relaxation times for carbons near the ester groups. Notable improvements compared to the additive C36 force field were obtained for membrane dipole potentials, lipid diffusion coeffs., and water permeability with the exception of monounsatd. lipid bilayers. It is anticipated that the optimized polarizable Drude2023 force field will help generate more accurate mol. simulations of pure bilayers and heterogeneous systems contg. membranes, advancing our understanding of the role of electronic polarization in these systems.
27. 27

    Chu, H.; Peng, X.; Li, Y.; Zhang, Y.; Min, H.; Li, G. Polarizable atomic multipole-based force field for DOPC and POPE membrane lipids. Mol. Phys. 2018, 116, 1037– 1050,  DOI: 10.1080/00268976.2018.1436201

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    Polarizable atomic multipole-based force field for DOPC and POPE membrane lipids

    Chu, Huiying; Peng, Xiangda; Li, Yan; Zhang, Yuebin; Min, Hanyi; Li, Guohui

    Molecular Physics (2018), 116 (7-8), 1037-1050CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)

    A polarizable at. multipole-based force field for the membrane bilayer models 1,2-dioleoyl-phosphocholine (DOPC) and 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE) has been developed. The force field adopts the same framework as the Atomic Multipole Optimized Energetics for Biomol. Applications (AMOEBA) model, in which the charge distribution of each atom is represented by the permanent at. monopole, dipole and quadrupole moments. Many-body polarization including the inter- and intra-mol. polarization is modelled in a consistent manner with distributed at. polarizabilities. The van der Waals parameters were first transferred from existing AMOEBA parameters for small org. mols. and then optimized by fitting to ab initio intermol. interaction energies between models and a water mol. Mol. dynamics simulations of the two aq. DOPC and POPE membrane bilayer systems, consisting of 72 model mols., were then carried out to validate the force field parameters. Membrane width, area per lipid, vol. per lipid, deuterium order parameters, electron d. profile, etc. were consistent with exptl. values.
28. 28

    Lucas, T. R.; Bauer, B. A.; Patel, S. Charge equilibration force fields for molecular dynamics simulations of lipids, bilayers, and integral membrane protein systems. Biochimica et Biophysica Acta (BBA)-Biomembranes 2012, 1818, 318– 329,  DOI: 10.1016/j.bbamem.2011.09.016

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    28

    Charge equilibration force fields for molecular dynamics simulations of lipids, bilayers, and integral membrane protein systems

    Lucas, Timothy R.; Bauer, Brad A.; Patel, Sandeep

    Biochimica et Biophysica Acta, Biomembranes (2012), 1818 (2), 318-329CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)

    A review. With the continuing advances in computational hardware and novel force fields constructed using quantum mechanics, the outlook for nonadditive force fields is promising. The authors' work in the past several years has demonstrated the utility of polarizable force fields, those based on the charge equilibration formalism, for a broad range of phys. and biophys. systems. The authors have constructed and applied polarizable force fields for lipids and lipid bilayers. In this review of the their recent work, the authors discuss the formalism they have adopted for implementing the charge equilibration (CHEQ) method for lipid mols. The authors discuss the methodol., related issues, and briefly discuss results from recent applications of such force fields. Application areas include DPPC-water monolayers, potassium ion permeation free energetics in the gramicidin A bacterial channel, and free energetics of permeation of charged amino acid analogs across the water-bilayer interface. This article is part of a Special Issue entitled: Membrane protein structure and function.
29. 29

    Ponder, J. W.; Wu, C.; Ren, P.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A., Jr Current status of the AMOEBA polarizable force field. J. Phys. Chem. B 2010, 114, 2549– 2564,  DOI: 10.1021/jp910674d

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    Current Status of the AMOEBA Polarizable Force Field

    Ponder, Jay W.; Wu, Chuanjie; Ren, Pengyu; Pande, Vijay S.; Chodera, John D.; Schnieders, Michael J.; Haque, Imran; Mobley, David L.; Lambrecht, Daniel S.; Di Stasio, Robert A.; Head-Gordon, Martin; Clark, Gary N. I.; Johnson, Margaret E.; Head-Gordon, Teresa

    Journal of Physical Chemistry B (2010), 114 (8), 2549-2564CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)

    A review. Mol. force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models toward more intricate and expensive polarizable models that should allow more accurate description of mol. properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theor. model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small mol. structural and thermodn. observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small mols., dynamical properties away from ambient conditions, and possible improvements in arom. interactions. State of the art electronic structure calcns. reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be esp. successful on protein-ligand binding and computational X-ray crystallog. where polarization and accurate electrostatics are crit.
30. 30

    Patel, S.; Brooks, C. L., III CHARMM fluctuating charge force field for proteins: I parameterization and application to bulk organic liquid simulations. Journal of computational chemistry 2004, 25, 1– 16,  DOI: 10.1002/jcc.10355

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    Duboué-Dijon, E.; Javanainen, M.; Delcroix, P.; Jungwirth, P.; Martinez-Seara, H. A practical guide to biologically relevant molecular simulations with charge scaling for electronic polarization. J. Chem. Phys. 2020, 153, 050901  DOI: 10.1063/5.0017775

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    A practical guide to biologically relevant molecular simulations with charge scaling for electronic polarization

    Duboue-Dijon, E.; Javanainen, M.; Delcroix, P.; Jungwirth, P.; Martinez-Seara, H.

    Journal of Chemical Physics (2020), 153 (5), 050901CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    A review. Mol. simulations can elucidate atomistic-level mechanisms of key biol. processes, which are often hardly accessible to expt. However, the results of the simulations can only be as trustworthy as the underlying simulation model. In many of these processes, interactions between charged moieties play a crit. role. Current empirical force fields tend to overestimate such interactions, often in a dramatic way, when polyvalent ions are involved. The source of this shortcoming is the missing electronic polarization in these models. Given the importance of such biomol. systems, there is great interest in fixing this deficiency in a computationally inexpensive way without employing explicitly polarizable force fields. Here, the authors review the electronic continuum correction approach, which accounts for electronic polarization in a mean-field way, focusing on its charge scaling variant. By pragmatically scaling only the charged mol. groups, the authors qual. improve the charge-charge interactions without extra computational costs and benefit from decades of force field development on biomol. force fields. (c) 2020 American Institute of Physics.
32. 32

    Botan, A.; Favela-Rosales, F.; Fuchs, P. F. J.; Javanainen, M.; Kanduč, M.; Kulig, W.; Lamberg, A.; Loison, C.; Lyubartsev, A.; Miettinen, M. S.; Monticelli, L.; Määttä, J.; Ollila, O. H. S.; Retegan, M.; Róg, T.; Santuz, H.; Tynkkynen, J. Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions. J. Phys. Chem. B 2015, 119, 15075– 15088,  DOI: 10.1021/acs.jpcb.5b04878

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    Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions

    Botan, Alexandru; Favela-Rosales, Fernando; Fuchs, Patrick F. J.; Javanainen, Matti; Kanduc, Matej; Kulig, Waldemar; Lamberg, Antti; Loison, Claire; Lyubartsev, Alexander; Miettinen, Markus S.; Monticelli, Luca; Maatta, Jukka; Ollila, O. H. Samuli; Retegan, Marius; Rog, Tomasz; Santuz, Hubert; Tynkkynen, Joona

    Journal of Physical Chemistry B (2015), 119 (49), 15075-15088CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Phospholipids are essential building blocks of biol. membranes. Despite a vast amt. of very accurate exptl. data, the atomistic resoln. structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resoln. mol. dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the exptl. data, but only if the simulations reproduce the data within exptl. accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR expts. in terms of the highly structurally sensitive C-H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resoln. structural accuracy of the models. Accurate models, in turn, allow mol. dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three-dimensional representation of biomols. in biol. relevant conditions. In addn. to lipid bilayers in fully hydrated conditions, we reviewed previous exptl. data for dehydrated bilayers and cholesterol-contg. bilayers, and interpreted them with simulations. Although none of the existing models reached exptl. accuracy, by critically comparing them we were able to distill relevant chem. information: (1) increase of choline order parameters indicates the P-N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files (https://zenodo.org/collection/user-nmrlipids) has become the most extensive publicly available collection of mol. dynamics simulation trajectories of lipid bilayers.
33. 33

    Catte, A.; Girych, M.; Javanainen, M.; Loison, C.; Melcr, J.; Miettinen, M. S.; Monticelli, L.; Määttä, J.; Oganesyan, V. S.; Ollila, O. H. S.; Tynkkynen, J.; Vilov, S. Molecular electrometer and binding of cations to phospholipid bilayers. Phys. Chem. Chem. Phys. 2016, 18, 32560– 32569,  DOI: 10.1039/C6CP04883H

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    Molecular electrometer and binding of cations to phospholipid bilayers

    Catte, Andrea; Girych, Mykhailo; Javanainen, Matti; Loison, Claire; Melcr, Josef; Miettinen, Markus S.; Monticelli, Luca; Maatta, Jukka; Oganesyan, Vasily S.; Ollila, O. H. Samuli; Tynkkynen, Joona; Vilov, Sergey

    Physical Chemistry Chemical Physics (2016), 18 (47), 32560-32569CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)

    Despite the vast amt. of exptl. and theor. studies on the binding affinity of cations, esp. the biol. relevant Na+ and Ca2+, for phospholipid bilayers, there is no consensus in the literature. By interpreting changes in the choline headgroup order parameters according to the mol. electrometer concept [Seelig et al., Biochem., 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and expts. The authors' findings strongly support the view that in contrast to Ca2+ and other multivalent ions, Na+ and other monovalent ions (except Li+) do not specifically bind to phosphatidylcholine lipid bilayers at sub-molar concns. However, the Na+ binding affinity was overestimated by several mol. dynamics simulation models, resulting in artificially pos. charged bilayers and exaggerated structural effects in the lipid headgroups. While a qual. correct headgroup order parameter response was obsd. with Ca2+ binding in all the tested models, no model had sufficient quant. accuracy to interpret the Ca2+:lipid stoichiometry or the induced atomistic resoln. structural changes. All scientific contributions to this open collaboration work were made public, using nmrlipids.blogspot.fi as the main communication platform.
34. 34

    Antila, H.; Buslaev, P.; Favela-Rosales, F.; Ferreira, T. M.; Gushchin, I.; Javanainen, M.; Kav, B.; Madsen, J. J.; Melcr, J.; Miettinen, M. S.; Määttä, J.; Nencini, R.; Ollila, O. H. S.; Piggot, T. J. Headgroup Structure and Cation Binding in Phosphatidylserine Lipid Bilayers. J. Phys. Chem. B 2019, 123, 9066– 9079,  DOI: 10.1021/acs.jpcb.9b06091

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    34

    Headgroup Structure and Cation Binding in Phosphatidylserine Lipid Bilayers

    Antila, Hanne; Buslaev, Pavel; Favela-Rosales, Fernando; Ferreira, Tiago M.; Gushchin, Ivan; Javanainen, Matti; Kav, Batuhan; Madsen, Jesper J.; Melcr, Josef; Miettinen, Markus S.; Maeaettae, Jukka; Nencini, Ricky; Ollila, O. H. Samuli; Piggot, Thomas J.

    Journal of Physical Chemistry B (2019), 123 (43), 9066-9079CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Phosphatidylserine (PS) is a neg. charged lipid type commonly found in eukaryotic membranes, where it interacts with proteins via nonspecific electrostatic interactions as well as via specific binding. Moreover, in the presence of calcium ions, PS lipids can induce membrane fusion and phase sepn. Mol. details of these phenomena remain poorly understood, partly because accurate models to interpret the exptl. data have not been available. Here the authors gather a set of previously published exptl. NMR data of C-H bond order parameter magnitudes, |S CH |, for pure PS and mixed PS:PC (phosphatidylcholine) lipid bilayers, and augment this data set by measuring the signs of S CH in the PS headgroup using S-DROSS solid-state NMR spectroscopy. The augmented data set is then used to assess the accuracy of the PS headgroup structures in, and the cation binding to, PS-contg. membranes in the most commonly used classical mol. dynamics (MD) force fields including CHARMM36, Lipid17, MacRog, Slipids, GROMOS-CKP, Berger, and variants. The authors show large discrepancies between different force fields, and that none of them reproduces the NMR data within exptl. accuracy. However, the best MD models can detect the most essential differences between PC and PS headgroup structures. The cation binding affinity is, in line with the previous results for PC lipids, not captured correctly by any of the PS force fields. Moreover, the simulated response of PS headgroup to bound ions can differ from expts. even qual. The collected exptl. dataset and simulation results will pave the way for development of lipid force fields that correctly describe the biol. relevant neg. charged membranes and their interactions with ions. This work is part of the NMRlipids open collaboration project (nmrlipids.blogspot.fi).
35. 35

    Bacle, A.; Buslaev, P.; Garcia-Fandino, R.; Favela-Rosales, F.; Mendes Ferreira, T.; Fuchs, P. F. J.; Gushchin, I.; Javanainen, M.; Kiirikki, A. M.; Madsen, J. J.; Melcr, J.; Milán Rodríguez, P.; Miettinen, M. S.; Ollila, O. H. S.; Papadopoulos, C. G.; Peón, A.; Piggot, T. J.; Piñeiro, Á.; Virtanen, S. I. Inverse Conformational Selection in Lipid–Protein Binding. J. Am. Chem. Soc. 2021, 143, 13701– 13709,  DOI: 10.1021/jacs.1c05549

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    35

    Inverse Conformational Selection in Lipid-Protein Binding

    Bacle, Amelie; Buslaev, Pavel; Garcia-Fandino, Rebeca; Favela-Rosales, Fernando; Mendes Ferreira, Tiago; Fuchs, Patrick F. J.; Gushchin, Ivan; Javanainen, Matti; Kiirikki, Anne M.; Madsen, Jesper J.; Melcr, Josef; Milan Rodriguez, Paula; Miettinen, Markus S.; Ollila, O. H. Samuli; Papadopoulos, Chris G.; Peon, Antonio; Piggot, Thomas J.; Pineiro, Angel; Virtanen, Salla I.

    Journal of the American Chemical Society (2021), 143 (34), 13701-13709CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Interest in lipid interactions with proteins and other biomols. is emerging not only in fundamental biochem. but also in the field of nanobiotechnol. where lipids are commonly used, for example, in carriers of mRNA vaccines. The outward-facing components of cellular membranes and lipid nanoparticles, the lipid headgroups, regulate membrane interactions with approaching substances, such as proteins, drugs, RNA, or viruses. Because lipid headgroup conformational ensembles were not exptl. detd. in physiol. relevant conditions, an essential question about their interactions with other biomols. remains unanswered: Do headgroups exchange between a few rigid structures, or fluctuate freely across a practically continuous spectrum of conformations. Here, the authors combine solid-state NMR expts. and mol. dynamics simulations from the NMRlipids Project to resolve the conformational ensembles of headgroups of four key lipid types in various biol. relevant conditions. Lipid headgroups sample a wide range of overlapping conformations in both neutral and charged cellular membranes, and differences in the headgroup chem. manifest only in probability distributions of conformations. Furthermore, the anal. of 894 protein-bound lipid structures from the Protein Data Bank suggests that lipids can bind to proteins in a wide range of conformations, which are not limited by the headgroup chem. The authors propose that lipids can select a suitable headgroup conformation from the wide range available to them to fit the various binding sites in proteins. The proposed inverse conformational selection model will extend also to lipid binding to targets other than proteins, such as drugs, RNA, and viruses.
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    Antila, H. S.; M. Ferreira, T.; Ollila, O. H. S.; Miettinen, M. S. Using Open Data to Rapidly Benchmark Biomolecular Simulations: Phospholipid Conformational Dynamics. J. Chem. Inf. Model. 2021, 61, 938– 949,  DOI: 10.1021/acs.jcim.0c01299

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    36

    Using open data to rapidly benchmark biomolecular simulations: phospholipid conformational dynamics

    Antila, Hanne S.; Ferreira, Tiago M.; Ollila, O. H. Samuli; Miettinen, Markus S.

    Journal of Chemical Information and Modeling (2021), 61 (2), 938-949CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

    Mol. dynamics (MD) simulations are widely used to monitor time-resolved motions of biomacromols., although it often remains unknown how closely the conformational dynamics correspond to those occurring in real life. Here, the authors used a large set of open-access MD trajectories of phosphatidylcholine (PC) lipid bilayers to benchmark the conformational dynamics in several contemporary MD models (force fields) against NMR data available in the literature: effective correlation times and spin-lattice relaxation rates. The authors found none of the tested MD models to fully reproduce the conformational dynamics. That said, the dynamics in CHARMM36 and Slipids are more realistic than in the Amber Lipid14, OPLS-based MacRog, and GROMOS-based Berger force fields, whose sampling of the glycerol backbone conformations is too slow. The performance of CHARMM36 persists when cholesterol is added to the bilayer, and when the hydration level is reduced. However, for conformational dynamics of the PC headgroup, both with and without cholesterol, Slipids provides the most realistic description because CHARMM36 overestimates the relative wt. of ~ 1 ns processes in the headgroup dynamics. The authors stress that not a single new simulation was run for the present work. This demonstrates the worth of open-access MD trajectory databanks for the indispensable step of any serious MD study: benchmarking the available force fields. The authors believe this proof of principle will inspire other novel applications of MD trajectory databanks and thus aid in developing biomol. MD simulations into a true computational microscope-not only for lipid membranes but for all biomacromol. systems.
37. 37

    Antila, H. S.; Kav, B.; Miettinen, M. S.; Martinez-Seara, H.; Jungwirth, P.; Ollila, O. H. S. Emerging Era of Biomolecular Membrane Simulations: Automated Physically-Justified Force Field Development and Quality-Evaluated Databanks. J. Phys. Chem. B 2022, 126, 4169– 4183,  DOI: 10.1021/acs.jpcb.2c01954

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    Emerging Era of Biomolecular Membrane Simulations: Automated Physically-Justified Force Field Development and Quality-Evaluated Databanks

    Antila, Hanne S.; Kav, Batuhan; Miettinen, Markus S.; Martinez-Seara, Hector; Jungwirth, Pavel; Ollila, O. H. Samuli

    Journal of Physical Chemistry B (2022), 126 (23), 4169-4183CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Mol. simulations of biol. membranes and proxies thereof are entering a new era characterized by several key aspects. Progress starts with the realization that the outcome of the simulations can only be as good as the underlying force field, and we actually need to know precisely how good or bad the results are. Therefore, standardized procedures for data quality evaluation are being established and will be applied to biomembrane simulations available in the literature. This provides the necessary basis and impetus for new force field development. Here, we propose the systematic buildup of phys. well-justified models that effectively account for the electronic polarization effects for all components of the biomembrane systems in aq. environments. Such a massive task can only be achieved within a reasonable time scale by applying automated parametrization tools.
38. 38

    Kurki, M.; Poso, A.; Bartos, P.; Miettinen, M. S. Structure of POPC Lipid Bilayers in OPLS3e Force Field. J. Chem. Inf. Model. 2022, 62, 6462– 6474,  DOI: 10.1021/acs.jcim.2c00395

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    Structure of POPC Lipid Bilayers in OPLS3e Force Field

    Kurki, Milla; Poso, Antti; Bartos, Piia; Miettinen, Markus S.

    Journal of Chemical Information and Modeling (2022), 62 (24), 6462-6474CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

    It is crucial for mol. dynamics simulations of biomembranes that the force field parameters give a realistic model of the membrane behavior. The authors examd. the OPLS3e force field for the carbon-hydrogen order parameters SCH of POPC (1-palmitoyl-2-oleoylphosphatidylcholine) lipid bilayers at varying hydration conditions and ion concns. OPLS3e behaves similarly to the CHARMM36 force field and relatively accurately follows the exptl. measured SCH for the lipid headgroup, the glycerol backbone, and the acyl tails. Thus, OPLS3e is a good choice for POPC bilayer simulations under many biol. relevant conditions. The exception are systems with an abundancy of ions, as similarly to most other force fields OPLS3e strongly overestimates the membrane-binding of cations, esp. Ca2+. This leads to undesirable pos. charge of the membrane surface and drastically lowers the concn. of Ca2+ in the surrounding solvent, which might cause issues in systems sensitive to correct charge distribution profiles across the membrane. Response of the headgroup order parameters SβCH and SαCH to decreasing hydration level. Exptl. values for POPC (2H NMR) at 296 K are from ref. Notably, small changes in temp. seem not to have a major effect on SCH, see Figures S10 and S11.
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    Javanainen, M.; Heftberger, P.; Madsen, J. J.; Miettinen, M. S.; Pabst, G.; Ollila, O. H. S. Quantitative Comparison against Experiments Reveals Imperfections in Force Fields’Descriptions of POPC–Cholesterol Interactions. J. Chem. Theory Comput. 2023, 19, 6342– 6352,  DOI: 10.1021/acs.jctc.3c00648

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40. 40

    Kiirikki, A. M.; Antila, H. S.; Bort, L. S.; Buslaev, P.; Favela-Rosales, F.; Ferreira, T. M.; Fuchs, P. F. J.; Garcia-Fandino, R.; Gushchin, I.; Kav, B.; Kucerka, N.; Kula, P.; Kurki, M.; Kuzmin, A.; Lalitha, A.; Lolicato, F.; Madsen, J. J.; Miettinen, M. S.; Mingham, C.; Monticelli, L.; Nencini, R.; Nesterenko, A. M.; Piggot, T. J.; Pineiro, A.; Reuter, N.; Samantray, S.; Suarez-Leston, F.; Talandashti, R.; Ollila, O. H. S. Overlay databank unlocks data-driven analyses of biomolecules for all. Nat Commun. 2024, 15 (1), 1136,  DOI: 10.1038/s41467-024-45189-z

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    Ferreira, T. M.; Ollila, O. H. S.; Pigliapochi, R.; Dabkowska, A. P.; Topgaard, D. Model-free estimation of the effective correlation time for C-H bond reorientation in amphiphilic bilayers: ¹H-¹³C solid-state NMR and MD simulations. J. Chem. Phys. 2015, 142, 044905  DOI: 10.1063/1.4906274

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    Model-free estimation of the effective correlation time for C-H bond reorientation in amphiphilic bilayers: 1H-13C solid-state NMR and MD simulations

    Ferreira, Tiago Mendes; Ollila, O. H. Samuli; Pigliapochi, Roberta; Dabkowska, Aleksandra P.; Topgaard, Daniel

    Journal of Chemical Physics (2015), 142 (4), 044905/1-044905/10CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    Mol. dynamics (MD) simulations give atomically detailed information on structure and dynamics in amphiphilic bilayer systems on timescales up to about 1 μs. The reorientational dynamics of the C-H bonds is conventionally verified by measurements of 13C or 2H NMR longitudinal relaxation rates R1, which are more sensitive to motional processes with correlation times close to the inverse Larmor frequency, typically around 1-10 ns on std. NMR instrumentation, and are thus less sensitive to the 10-1000 ns timescale motion that can be obsd. in the MD simulations. We propose an exptl. procedure for atomically resolved model-free estn. of the C-H bond effective reorientational correlation time τe, which includes contributions from the entire range of all-atom MD timescales and that can be calcd. directly from the MD trajectories. The approach is based on measurements of 13C R1 and R1ρ relaxation rates, as well as 1H-13C dipolar couplings, and is applicable to anisotropic liq. cryst. lipid or surfactant systems using a conventional solid-state NMR spectrometer and samples with natural isotopic compn. The procedure is demonstrated on a fully hydrated lamellar phase of 1-palmitoyl-2-oleoyl-phosphatidylcholine, yielding values of τe from 0.1 ns for the Me groups in the choline moiety and at the end of the acyl chains to 3 ns for the g1 methylene group of the glycerol backbone. MD simulations performed with a widely used united-atom force-field reproduce the τe-profile of the major part of the acyl chains but underestimate the dynamics of the glycerol backbone and adjacent mol. segments. The measurement of exptl. τe-profiles can be used to study subtle effects on C-H bond reorientational motions in anisotropic liq. crystals, as well as to validate the C-H bond reorientation dynamics predicted in MD simulations of amphiphilic bilayers such as lipid membranes. (c) 2015 American Institute of Physics.
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    Eastman, P.; Swails, J.; Chodera, J. D.; McGibbon, R. T.; Zhao, Y.; Beauchamp, K. A.; Wang, L.-P.; Simmonett, A. C.; Harrigan, M. P.; Stern, C. D. OpenMM 7: Rapid development of high performance algorithms for molecular dynamics. PLoS computational biology 2017, 13, e1005659  DOI: 10.1371/journal.pcbi.1005659

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    OpenMM 7: Rapid development of high performance algorithms for molecular dynamics

    Eastman, Peter; Swails, Jason; Chodera, John D.; McGibbon, Robert T.; Zhao, Yutong; Beauchamp, Kyle A.; Wang, Lee-Ping; Simmonett, Andrew C.; Harrigan, Matthew P.; Stern, Chaya D.; Wiewiora, Rafal P.; Brooks, Bernard R.; Pande, Vijay S.

    PLoS Computational Biology (2017), 13 (7), e1005659/1-e1005659/17CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)

    OpenMM is a mol. dynamics simulation toolkit with a unique focus on extensibility. It allows users to easily add new features, including forces with novel functional forms, new integration algorithms, and new simulation protocols. Those features automatically work on all supported hardware types (including both CPUs and GPUs) and perform well on all of them. In many cases they require minimal coding, just a math. description of the desired function. They also require no modification to OpenMM itself and can be distributed independently of OpenMM. This makes it an ideal tool for researchers developing new simulation methods, and also allows those new methods to be immediately available to the larger community.
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    Phillips, J. C.; Hardy, D. J.; Maia, J. D.; Stone, J. E.; Ribeiro, J. V.; Bernardi, R. C.; Buch, R.; Fiorin, G.; Hénin, J.; Jiang, W. 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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    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, 19– 25,  DOI: 10.1016/j.softx.2015.06.001

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    Gromacs Drude. https://github.com/gromacs/gromacs/tree/drude.

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    Rackers, J. A.; Wang, Z.; Lu, C.; Laury, M. L.; Lagardère, L.; Schnieders, M. J.; Piquemal, J.-P.; Ren, P.; Ponder, J. W. Tinker 8: software tools for molecular design. J. Chem. Theory Comput. 2018, 14, 5273– 5289,  DOI: 10.1021/acs.jctc.8b00529

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    Tinker 8: Software Tools for Molecular Design

    Rackers, Joshua A.; Wang, Zhi; Lu, Chao; Laury, Marie L.; Lagardere, Louis; Schnieders, Michael J.; Piquemal, Jean-Philip; Ren, Pengyu; Ponder, Jay W.

    Journal of Chemical Theory and Computation (2018), 14 (10), 5273-5289CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    The Tinker software, currently released as version 8, is a modular mol. mechanics and dynamics package written primarily in a std., easily portable dialect of Fortran 95 with OpenMP extensions. CIt supports a wide variety of force fields, including polarizable models such as the Atomic Multipole Optimized Energetics for Biomol. Applicatons (AMOEBA) force field. The package runs on Linux, macOS and Windows systems. In addn. to canonical Tinker, there are branches, Tinker-HP and Tinker-OpenMM, designed for use on MPI-parallel distributed memory supercomputers and state-of-the-art graphical processing units (GPUs), resp. The Tinker suite also includes a tightly integrated Java-based graphical user interface called Force Field Explorer (FFE), which provides mol. visualization capabilities as well as the ability to launch and control Tinker calcns.
47. 47

    Jo, S.; Kim, T.; Iyer, V. G.; Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. Journal of computational chemistry 2008, 29, 1859– 1865,  DOI: 10.1002/jcc.20945

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    CHARMM-GUI: a web-based graphical user interface for CHARMM

    Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.; Im, Wonpil

    Journal of Computational Chemistry (2008), 29 (11), 1859-1865CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    CHARMM is an academic research program used widely for macromol. mechanics and dynamics with versatile anal. and manipulation tools of at. coordinates and dynamics trajectories. CHARMM-GUI, http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate various input files and mol. systems to facilitate and standardize the usage of common and advanced simulation techniques in CHARMM. The web environment provides an ideal platform to build and validate a mol. model system in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the previous setup and regenerate the whole system again. In this article, we describe the currently available functional modules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future directions of the CHARMM-GUI development project are also discussed briefly together with other features in the CHARMM-GUI website, such as Archive and Movie Gallery.
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    Lee, J.; Cheng, X.; Swails, J. M.; Yeom, M. S.; Eastman, P. K.; Lemkul, J. A.; Wei, S.; Buckner, J.; Jeong, J. C.; Qi, Y. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J. Chem. Theory Comput. 2016, 12, 405– 413,  DOI: 10.1021/acs.jctc.5b00935

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    CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field

    Lee, Jumin; Cheng, Xi; Swails, Jason M.; Yeom, Min Sun; Eastman, Peter K.; Lemkul, Justin A.; Wei, Shuai; Buckner, Joshua; Jeong, Jong Cheol; Qi, Yifei; Jo, Sunhwan; Pande, Vijay S.; Case, David A.; Brooks, Charles L.; MacKerell, Alexander D.; Klauda, Jeffery B.; Im, Wonpil

    Journal of Chemical Theory and Computation (2016), 12 (1), 405-413CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Proper treatment of nonbonded interactions is essential for the accuracy of mol. dynamics (MD) simulations, esp. in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain satn. and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the std. protocol used in CHARMM as well as from expts. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with exptl. data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential vs. a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small mols.
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    Kognole, A. A.; Lee, J.; Park, S.-J.; Jo, S.; Chatterjee, P.; Lemkul, J. A.; Huang, J.; MacKerell, A. D., Jr; Im, W. CHARMM-GUI Drude prepper for molecular dynamics simulation using the classical Drude polarizable force field. Journal of computational chemistry 2022, 43, 359– 375,  DOI: 10.1002/jcc.26795

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    OpenMM Scripts for AMOEBA Force Field MD Simulations. https://github.com/Inniag/openmm-scripts-amoeba.

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    Wu, E. L.; Cheng, X.; Jo, S.; Rui, H.; Song, K. C.; Davila-Contreras, E. M.; Qi, Y.; Lee, J.; Monje-Galvan, V.; Venable, R. M.; Klauda, J. B.; Im, W. CHARMM-GUI membrane builder toward realistic biological membrane simulations. J. Comput. Chem. 2014, 35, 1997– 2004,  DOI: 10.1002/jcc.23702

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    CHARMM-GUI Membrane Builder toward realistic biological membrane simulations

    Wu, Emilia L.; Cheng, Xi; Jo, Sunhwan; Rui, Huan; Song, Kevin C.; Davila-Contreras, Eder M.; Qi, Yifei; Lee, Jumin; Monje-Galvan, Viviana; Venable, Richard M.; Klauda, Jeffery B.; Im, Wonpil

    Journal of Computational Chemistry (2014), 35 (27), 1997-2004CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    CHARMM-GUI Membrane Builder,http://www.charmm-gui.org/input/membrane, is a web-based user interface designed to interactively build all-atom protein/membrane or membrane-only systems for mol. dynamics simulations through an automated optimized process. In this work, we describe the new features and major improvements in Membrane Builder that allow users to robustly build realistic biol. membrane systems, including (1) addn. of new lipid types, such as phosphoinositides, cardiolipin (CL), sphingolipids, bacterial lipids, and ergosterol, yielding more than 180 lipid types, (2) enhanced building procedure for lipid packing around protein, (3) reliable algorithm to detect lipid tail penetration to ring structures and protein surface, (4) distance-based algorithm for faster initial ion displacement, (5) CHARMM inputs for P21 image transformation, and (6) NAMD equilibration and prodn. inputs. The robustness of these new features is illustrated by building and simulating a membrane model of the polar and septal regions of E. coli membrane, which contains five lipid types: CL lipids with two types of acyl chains and phosphatidylethanolamine lipids with three types of acyl chains. It is our hope that CHARMM-GUI Membrane Builder becomes a useful tool for simulation studies to better understand the structure and dynamics of proteins and lipids in realistic biol. membrane environments.
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    Jo, S.; Lim, J. B.; Klauda, J. B.; Im, W. CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes. Biophysical journal 2009, 97, 50– 58,  DOI: 10.1016/j.bpj.2009.04.013

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    CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes

    Jo, Sunhwan; Lim, Joseph B.; Klauda, Jeffery B.; Im, Wonpil

    Biophysical Journal (2009), 97 (1), 50-58CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

    The CHARMM-GUI Membrane Builder (http://www.charmm-gui.org/input/membrane), an intuitive, straightforward, web-based graphical user interface, was expanded to automate the building process of heterogeneous lipid bilayers, with or without a protein and with support for up to 32 different lipid types. The efficacy of these new features was tested by building and simulating lipid bilayers that resemble yeast membranes, composed of cholesterol, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, palmitoyloleoylphosphatidylethanolamine, palmitoyloleoylphosphatidylamine, and palmitoyloleoylphosphatidylserine. Four membranes with varying concns. of cholesterol and phospholipids were simulated, for a total of 170 ns at 303.15 K. Unsatd. phospholipid chain concn. had the largest influence on membrane properties, such as av. lipid surface area, d. profiles, deuterium order parameters, and cholesterol tilt angle. Simulations with a high concn. of unsatd. chains (73%, membraneunsat) resulted in a significant increase in lipid surface area and a decrease in deuterium order parameters, compared with membranes with a high concn. of satd. chains (60-63%, membranesat). The av. tilt angle of cholesterol with respect to bilayer normal was largest, and the distribution was significantly broader for membraneunsat. Moreover, short-lived cholesterol orientations parallel to the membrane surface existed only for membraneunsat. The membranesat simulations were in a liq.-ordered state, and agree with similar exptl. cholesterol-contg. membranes.
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    Jo, S.; Kim, T.; Im, W. Automated builder and database of protein/membrane complexes for molecular dynamics simulations. PLoS one 2007, 2, e880  DOI: 10.1371/journal.pone.0000880

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    Automated builder and database of protein/membrane complexes for molecular dynamics simulations

    Jo Sunhwan; Kim Taehoon; Im Wonpil

    PloS one (2007), 2 (9), e880 ISSN:.

    Molecular dynamics simulations of membrane proteins have provided deeper insights into their functions and interactions with surrounding environments at the atomic level. However, compared to solvation of globular proteins, building a realistic protein/membrane complex is still challenging and requires considerable experience with simulation software. Membrane Builder in the CHARMM-GUI website (http://www.charmm-gui.org) helps users to build such a complex system using a web browser with a graphical user interface. Through a generalized and automated building process including system size determination as well as generation of lipid bilayer, pore water, bulk water, and ions, a realistic membrane system with virtually any kinds and shapes of membrane proteins can be generated in 5 minutes to 2 hours depending on the system size. Default values that were elaborated and tested extensively are given in each step to provide reasonable options and starting points for both non-expert and expert users. The efficacy of Membrane Builder is illustrated by its applications to 12 transmembrane and 3 interfacial membrane proteins, whose fully equilibrated systems with three different types of lipid molecules (DMPC, DPPC, and POPC) and two types of system shapes (rectangular and hexagonal) are freely available on the CHARMM-GUI website. One of the most significant advantages of using the web environment is that, if a problem is found, users can go back and re-generate the whole system again before quitting the browser. Therefore, Membrane Builder provides the intuitive and easy way to build and simulate the biologically important membrane system.
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    Lee, J.; Patel, D. S.; Ståhle, J.; Park, S.-J.; Kern, N. R.; Kim, S.; Lee, J.; Cheng, X.; Valvano, M. A.; Holst, O. CHARMM-GUI membrane builder for complex biological membrane simulations with glycolipids and lipoglycans. J. Chem. Theory Comput. 2019, 15, 775– 786,  DOI: 10.1021/acs.jctc.8b01066

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    CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans

    Lee, Jumin; Patel, Dhilon S.; Stahle, Jonas; Park, Sang-Jun; Kern, Nathan R.; Kim, Seonghoon; Lee, Joonseong; Cheng, Xi; Valvano, Miguel A.; Holst, Otto; Knirel, Yuriy A.; Qi, Yifei; Jo, Sunhwan; Klauda, Jeffery B.; Widmalm, Goran; Im, Wonpil

    Journal of Chemical Theory and Computation (2019), 15 (1), 775-786CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Glycolipids (such as glycoglycerolipids, glycosphingolipids, and glycosylphosphatidylinositol) and lipoglycans (such as lipopolysaccharides (LPS), lipooligosaccharides (LOS), mycobacterial lipoarabinomannan, and mycoplasma lipoglycans) are typically found on the surface of cell membranes and play crucial roles in various cellular functions. Characterizing their structure and dynamics at the mol. level is essential to understand their biol. roles, but systematic generation of glycolipid and lipoglycan structures is challenging because of great variations in lipid structures and glycan sequences (i.e., carbohydrate types and their linkages). To facilitate the generation of all-atom glycolipid/LPS/LOS structures, we have developed Glycolipid Modeler and LPS Modeler in CHARMM-GUI (http://www.charmm-gui.org), a web-based interface that simplifies building of complex biol. simulation systems. In addn., we have incorporated these modules into Membrane Builder so that users can readily build a complex sym. or asym. biol. membrane system with various glycolipids and LPS/LOS. These tools are expected to be useful in innovative and novel glycolipid/LPS/LOS modeling and simulation research by easing tedious and intricate steps in modeling complex biol. systems and shall provide insight into structures, dynamics, and underlying mechanisms of complex glycolipid-/LPS-/LOS-contg. biol. membrane systems.
55. 55

    Klauda, J. B.; Venable, R. M.; Freites, J. A.; O’Connor, J. W.; Tobias, D. J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A. D., Jr; 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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    55

    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.
56. 56

    Lin, F.-Y.; Lopes, P. E.; Harder, E.; Roux, B.; MacKerell, A. D., Jr Polarizable force field for molecular ions based on the classical Drude oscillator. J. Chem. Inf. Model. 2018, 58, 993– 1004,  DOI: 10.1021/acs.jcim.8b00132

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    56

    Polarizable Force Field for Molecular Ions Based on the Classical Drude Oscillator

    Lin, Fang-Yu; Lopes, Pedro E. M.; Harder, Edward; Roux, Benoit; MacKerell, Alexander D.

    Journal of Chemical Information and Modeling (2018), 58 (5), 993-1004CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

    Development of accurate force field parameters for mol. ions in the context of a polarizable energy function based on the classical Drude oscillator is a crucial step toward an accurate polarizable model for modeling and simulations of biol. macromols. Toward this goal the authors have undertaken a hierarchical approach in which force field parameter optimization is initially performed for small mols. for which exptl. data exists that serve as building blocks of macromol. systems. Small mols. representative of the ionic moieties of biol. macromols. include the cationic ammonium and Me substituted ammonium derivs., imidazolium, guanidinium and methylguanidinium, and the anionic acetate, phenolate, and alkanethiolates. In the present work, parameters for mol. ions in the context of the Drude polarizable force field are optimized and compared to results from the nonpolarizable additive CHARMM general force field (CGenFF). Electrostatic and Lennard-Jones parameters for the model compds. are developed in the context of the polarizable SWM4-NDP water model, with emphasis on assuring that the hydration free energies are consistent with previously reported parameters for at. ions. The final parameters are shown to be in good agreement with the selected quantum mech. (QM) and exptl. target data. Anal. of the structure of water around the ions reveals substantial differences between the Drude and additive force fields indicating the important role of polarization in dictating the mol. details of aq. solvation. The presented parameters represent the foundation for the charged functionalities in future generations of the Drude polarizable force field for biol. macromols. as well as for drug-like mols.
57. 57

    Lamoureux, G.; Harder, E.; Vorobyov, I. V.; Roux, B.; MacKerell, A. D., Jr A polarizable model of water for molecular dynamics simulations of biomolecules. Chem. Phys. Lett. 2006, 418, 245– 249,  DOI: 10.1016/j.cplett.2005.10.135

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    57

    A polarizable model of water for molecular dynamics simulations of biomolecules

    Lamoureux, Guillaume; Harder, Edward; Vorobyov, Igor V.; Roux, Benoit; MacKerell, Alexander D.

    Chemical Physics Letters (2006), 418 (1-3), 245-249CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)

    The SWM4-DP polarizable water model [G. Lamoureux, A.D. MacKerell, Jr., B. Roux, J. Chem. Phys. 119 (2003) 5185], based on classical Drude oscillators, is re-optimized for neg. charged Drude particles. The new model, called SWM4-NDP, will be incorporated into a polarizable biomol. force field currently in development. It is calibrated to reproduce important properties of the neat liq. at room temp. and pressure: vaporization enthalpy, d., static dielec. const. and self-diffusion const. In this Letter, we also show that it yields the correct liq. shear viscosity and free energy of hydration.
58. 58

    Brooks, B. R.; Brooks, C. L., III; Mackerell, A. D., Jr; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S. CHARMM: the biomolecular simulation program. Journal of computational chemistry 2009, 30, 1545– 1614,  DOI: 10.1002/jcc.21287

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    CHARMM: The biomolecular simulation program

    Brooks, B. R.; Brooks, C. L., III; Mackerell, A. D., Jr.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M.

    Journal of Computational Chemistry (2009), 30 (10), 1545-1614CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    A review. CHARMM (Chem. at HARvard Mol. Mechanics) is a highly versatile and widely used mol. simulation program. It has been developed over the last three decades with a primary focus on mols. of biol. interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small mol. ligands, as they occur in soln., crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, mol. minimization, dynamics, and anal. techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calcns. with CHARMM can be performed using a no. of different energy functions and models, from mixed quantum mech.-mol. mech. force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009.
59. 59

    Venable, R. M. OpenMM simulations of POPE using the CHARMM Drude2023 force field. 2023;  DOI: 10.5281/zenodo.7872447 .

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60. 60

    Venable, R. M. OpenMM simulations of POPC using the CHARMM Drude2023 force field. 2023;  DOI: 10.5281/zenodo.7871949 .

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    There is no corresponding record for this reference.
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    Åqvist, J.; Wennerström, P.; Nervall, M.; Bjelic, S.; Brandsdal, B. O. Molecular dynamics simulations of water and biomolecules with a Monte Carlo constant pressure algorithm. Chemical physics letters 2004, 384, 288– 294,  DOI: 10.1016/j.cplett.2003.12.039

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    Molecular dynamics simulations of water and biomolecules with a Monte Carlo constant pressure algorithm

    Aqvist, Johan; Wennerstrom, Petra; Nervall, Martin; Bjelic, Sinisa; Brandsdal, Bjorn O.

    Chemical Physics Letters (2004), 384 (4-6), 288-294CODEN: CHPLBC; ISSN:0009-2614. (Elsevier Science B.V.)

    A mixed mol. dynamics/Monte Carlo (MD/MC) algorithm for const. pressure simulations of arbitrary mol. systems is examd. Calcns. are reported at ambient and high pressures both for liq. water systems and for a chem. reaction step in a solvated enzyme utilizing empirical valence bond potentials. The present method reproduces earlier reported results well and is computationally efficient since it does not require the virial to be evaluated at each MD step. The effects of introducing MC vol. steps on the dynamics of the system are negligible provided that the vol. step sizes and updating frequencies are appropriately chosen.
62. 62

    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.
63. 63

    Wennberg, C. L.; Murtola, T.; Hess, B.; Lindahl, E. Lennard-Jones lattice summation in bilayer simulations has critical effects on surface tension and lipid properties. J. Chem. Theory Comput. 2013, 9, 3527– 3537,  DOI: 10.1021/ct400140n

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    Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties

    Wennberg, Christian L.; Murtola, Teemu; Hess, Berk; Lindahl, Erik

    Journal of Chemical Theory and Computation (2013), 9 (8), 3527-3537CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    The accuracy of electrostatic interactions in mol. dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto std. for most types of biomol. simulations, and in particular, for lipid bilayers, it has been a crit. improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long-range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approxn. for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calcns.
64. 64

    Lagardere, L.; Aviat, F.; Piquemal, J.-P. Pushing the limits of multiple-time-step strategies for polarizable point dipole molecular dynamics. journal of physical chemistry letters 2019, 10, 2593– 2599,  DOI: 10.1021/acs.jpclett.9b00901

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    Tuckerman, M.; Berne, B. J.; Martyna, G. J. Reversible multiple time scale molecular dynamics. J. Chem. Phys. 1992, 97, 1990– 2001,  DOI: 10.1063/1.463137

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    Reversible multiple time scale molecular dynamics

    Tuckerman, M.; Berne, B. J.; Martyna, G. J.

    Journal of Chemical Physics (1992), 97 (3), 1990-2001CODEN: JCPSA6; ISSN:0021-9606.

    The Trotter factorization of the Liouville propagator is used to generate new reversible mol. dynamics integrators. This strategy is applied to derive reversible ref. system propagator algorithms (RESPA) that greatly accelerate simulations of systems with a sepn. of time scales or with long range forces. The new algorithms have all of the advantages of previous RESPA integrators but are reversible, and more stable than those methods. These methods are applied to a set of paradigmatic systems and are shown to be superior to earlier methods. It is shown how the new RESPA methods are related to predictor-corrector integrators. These methods can be used to accelerate the integration of the equations of motion of systems with Nose thermostats.
66. 66

    Shi, Y.; Xia, Z.; Zhang, J.; Best, R.; Wu, C.; Ponder, J. W.; Ren, P. Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins. J. Chem. Theory Comput. 2013, 9, 4046– 4063,  DOI: 10.1021/ct4003702

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    Polarizable Atomic Multipole-Based AMOEBA Force Field for Proteins

    Shi, Yue; Xia, Zhen; Zhang, Jiajing; Best, Robert; Wu, Chuanjie; Ponder, Jay W.; Ren, Pengyu

    Journal of Chemical Theory and Computation (2013), 9 (9), 4046-4063CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Development of the AMOEBA (at. multipole optimized energetics for biomol. simulation) force field for proteins is presented. The current version (AMOEBA-2013) utilizes permanent electrostatic multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chem. and phys. environments. The at. multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mech. calcns. via a consistent and extensible protocol. Mol. polarizability is modeled via a Thole-style damped interactive induction model based upon distributed at. polarizabilities. Inter- and intramol. polarization is treated in a consistent fashion via the Thole model. The intramol. polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were detd. by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Mol. dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in soln. Overall the calcd. conformational free energies and J-coupling consts. are consistent with PDB statistics and exptl. NMR results, resp. In addn., the exptl. crystal structures of a no. of proteins are well maintained during mol. dynamics (MD) simulation. While further calcns. are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and soln. environments.
67. 67

    Laury, M. L.; Wang, L.-P.; Pande, V. S.; Head-Gordon, T.; Ponder, J. W. Revised parameters for the AMOEBA polarizable atomic multipole water model. J. Phys. Chem. B 2015, 119, 9423– 9437,  DOI: 10.1021/jp510896n

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    67

    Revised Parameters for the AMOEBA Polarizable Atomic Multipole Water Model

    Laury, Marie L.; Wang, Lee-Ping; Pande, Vijay S.; Head-Gordon, Teresa; Ponder, Jay W.

    Journal of Physical Chemistry B (2015), 119 (29), 9423-9437CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    A set of improved parameters for the AMOEBA polarizable at. multipole water model is developed. An automated procedure, ForceBalance, is used to adjust model parameters to enforce agreement with ab initio-derived results for water clusters and exptl. data for a variety of liq. phase properties across a broad temp. range. The values reported here for the new AMOEBA14 water model represent a substantial improvement over the previous AMOEBA03 model. The AMOEBA14 model accurately predicts the temp. of max. d. and qual. matches the exptl. d. curve across temps. from 249 to 373 K. Excellent agreement is obsd. for the AMOEBA14 model in comparison to exptl. properties as a function of temp., including the second virial coeff., enthalpy of vaporization, isothermal compressibility, thermal expansion coeff., and dielec. const. The viscosity, self-diffusion const., and surface tension are also well reproduced. In comparison to high-level ab initio results for clusters of 2-20 water mols., the AMOEBA14 model yields results similar to AMOEBA03 and the direct polarization iAMOEBA models. With advances in computing power, calibration data, and optimization techniques, we recommend the use of the AMOEBA14 water model for future studies employing a polarizable water model.
68. 68

    Rackers, J. A.; Silva, R. R.; Wang, Z.; Ponder, J. W. Polarizable water potential derived from a model electron density. J. Chem. Theory Comput. 2021, 17, 7056– 7084,  DOI: 10.1021/acs.jctc.1c00628

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    68

    Polarizable Water Potential Derived from a Model Electron Density

    Rackers, Joshua A.; Silva, Roseane R.; Wang, Zhi; Ponder, Jay W.

    Journal of Chemical Theory and Computation (2021), 17 (11), 7056-7084CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    A new empirical potential for efficient, large scale mol. dynamics simulation of water is presented. The HIPPO (Hydrogen-like Intermol. Polarizable POtential) force field is based upon the model electron d. of a hydrogen-like atom. This framework is used to derive and parametrize individual terms describing charge penetration damped permanent electrostatics, damped polarization, charge transfer, anisotropic Pauli repulsion, and damped dispersion interactions. Initial parameter values were fit to Symmetry Adapted Perturbation Theory (SAPT) energy components for ten water dimer configurations, as well as the radial and angular dependence of the canonical dimer. The SAPT-based parameters were then systematically refined to extend the treatment to water bulk phases. The final HIPPO water model provides a balanced representation of a wide variety of properties of gas phase clusters, liq. water, and ice polymorphs, across a range of temps. and pressures. This water potential yields a rationalization of water structure, dynamics, and thermodn. explicitly correlated with an ab initio energy decompn., while providing a level of accuracy comparable or superior to previous polarizable at. multipole force fields. The HIPPO water model serves as a cornerstone around which similarly detailed physics-based models can be developed for addnl. mol. species.
69. 69

    Mauger, N.; Plé, T.; Lagardère, L.; Huppert, S.; Piquemal, J.-P. Improving condensed-phase water dynamics with explicit nuclear quantum effects: The polarizable Q-AMOEBA force field. J. Phys. Chem. B 2022, 126, 8813– 8826,  DOI: 10.1021/acs.jpcb.2c04454

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    69

    Improving Condensed-Phase Water Dynamics with Explicit Nuclear Quantum Effects: The Polarizable Q-AMOEBA Force Field

    Mauger, Nastasia; Ple, Thomas; Lagardere, Louis; Huppert, Simon; Piquemal, Jean-Philip

    Journal of Physical Chemistry B (2022), 126 (43), 8813-8826CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    We introduce a new parametrization of the AMOEBA polarizable force field for water denoted Q-AMOEBA, for use in simulations that explicitly account for nuclear quantum effects (NQEs). This study is made possible thanks to the recently introduced adaptive Quantum Thermal Bath (adQTB) simulation technique which computational cost is comparable to classical mol. dynamics. The flexible Q-AMOEBA model conserves the initial AMOEBA functional form, with an intermol. potential including an at. multipole description of electrostatic interactions (up to quadrupole), a polarization contribution based on the Thole interaction model and a buffered 14-7 potential to model van der Waals interactions. It has been obtained by using a ForceBalance fitting strategy including high-level quantum chem. ref. energies and selected condensed-phase properties targets. The final Q-AMOEBA model is shown to accurately reproduce both gas-phase and condensed-phase properties, notably improving the original AMOEBA water model. This development allows the fine study of NQEs on water liq. phase properties such as the av. H-O-H angle compared to its gas-phase equil. value, isotope effects, and so on. Q-AMOEBA also provides improved IR spectroscopy prediction capabilities compared to AMOEBA03. Overall, we show that the impact of NQEs depends on the underlying model functional form and on the assocd. strength of hydrogen bonds. Since adQTB simulations can be performed at near classical computational cost using the Tinker-HP package, Q-AMOEBA can be extended to org. mols., proteins, and nucleic acids opening the possibility for the large-scale study of the importance of NQEs in biophysics.
70. 70

    Mao, Y.; Demerdash, O.; Head-Gordon, M.; Head-Gordon, T. Assessing ion–water interactions in the AMOEBA force field using energy decomposition analysis of electronic structure calculations. J. Chem. Theory Comput. 2016, 12, 5422– 5437,  DOI: 10.1021/acs.jctc.6b00764

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    70

    Assessing Ion-Water Interactions in the AMOEBA Force Field Using Energy Decomposition Analysis of Electronic Structure Calculations

    Mao, Yuezhi; Demerdash, Omar; Head-Gordon, Martin; Head-Gordon, Teresa

    Journal of Chemical Theory and Computation (2016), 12 (11), 5422-5437CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    AMOEBA is a mol. mechanics force field that addresses some of the shortcomings of a fixed partial charge model, by including permanent at. point multipoles through quadrupoles, as well as many-body polarization through the use of point inducible dipoles. In this work, we investigate how well AMOEBA formulates its non-bonded interactions, and how it implicitly incorporates quantum mech. effects such as charge penetration (CP) and charge transfer (CT), for water-water and water-ion interactions. We find that AMOEBA's total interaction energies, as a function of distance and over angular scans for the water dimer and for a range of water-monovalent cations, agree well with an advanced d. functional theory (DFT) model, whereas the water-halides and water-divalent cations show significant disagreement with the DFT result, esp. in the compressed region when the two fragments overlap. We use a second-generation energy decompn. anal. (EDA) scheme based on absolutely localized MOs (ALMOs) to show that in the best cases AMOEBA relies on cancellation of errors by softening of the van der Waals (vdW) wall to balance permanent electrostatics that are too unfavorable, thereby compensating for the missing CP effect. CT, as another important stabilizing effect not explicitly taken into account in AMOEBA, is also found to be incorporated by the softened vdW interaction. For the water-halides and water-divalent cations, this compensatory approach is not as well executed by AMOEBA over all distances and angles, wherein permanent electrostatics remains too unfavorable and polarization is overdamped in the former while overestimated in the latter. We conclude that the DFT-based EDA approach can help refine a next-generation AMOEBA model that either realizes a better cancellation of errors for problematic cases like those illustrated here, or serves to guide the parametrization of explicit functional forms for short-range contributions from CP and/or CT.
71. 71

    Yu, W.; Lopes, P. E.; Roux, B.; MacKerell, A. D. Six-site polarizable model of water based on the classical Drude oscillator. J. Chem. Phys. 2013, 138, 034508,  DOI: 10.1063/1.4774577

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    71

    Six-site polarizable model of water based on the classical Drude oscillator

    Yu, Wenbo; Lopes, Pedro E. M.; Roux, Benoit; MacKerell, Alexander D., Jr.

    Journal of Chemical Physics (2013), 138 (3), 034508/1-034508/13CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    A polarizable water model, SWM6, was developed and optimized for liq. phase simulations under ambient conditions. Building upon the previously developed SWM4-NDP model, addnl. sites representing oxygen lone-pairs were introduced. The geometry of the sites is assumed to be rigid. Considering the large no. of adjustable parameters, simulated annealing together with polynomial fitting was used to facilitate model optimization. The new water model was shown to yield the correct self-diffusion coeff. after taking the system size effect into account, and the dimer geometry is better reproduced than in the SWM4 models. Moreover, the exptl. oxygen-oxygen radial distribution is better reproduced, indicating that the new model more accurately describes the local hydrogen bonding structure of bulk phase water. This was further validated by its ability to reproduce the exptl. nuclear magnetic shielding and related chem. shift of the water hydrogen in the bulk phase, a property sensitive to the local hydrogen bonding structure. In addn., comparison of the liq. properties of the SWM6 model is made with those of a no. of widely used additive and polarizable models. Overall, improved balance between the description of monomer, dimer, clustered, and bulk phase water is obtained with the new model compared to its SWM4-NDP polarizable predecessor, though application of the model requires an approx. twofold increase on computational resources. (c) 2013 American Institute of Physics.
72. 72

    Xiong, Y.; Onufriev, A. V. Exploring optimization strategies for improving explicit water models: Rigid n-point model and polarizable model based on Drude oscillator. PLoS One 2019, 14, e0224991  DOI: 10.1371/journal.pone.0224991

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    72

    Exploring optimization strategies for improving explicit water models: Rigid n-point model and polarizable model based on Drude oscillator

    Xiong, Yeyue; Onufriev, Alexey V.

    PLoS One (2019), 14 (11), e0224991CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    In an effort to provide guidance for model development, here we have explored the limiting accuracy of "electrostatically globally optimal" n-point water models in terms of their ability to reproduce properties of water dimer-a mimic of the condensed state of water. For a given n, each model is built upon a set of ref. multipole moments (e.g. abinitio) and then optimized to reproduce water dimer total dipole moment. We find that global optimization of the charge distribution alone can deliver high accuracy of the water model: for n = 4 or n = 5, the geometry of the resulting water dimer can be almost within 50 of the ab initio ref., which is half that of the exptl. error margin. The resulting model (n = 3) shows a relatively small improvement in accuracy, suggesting that the strategy of merely adding the polarizability to an inferior accuracy water model used as the base cannot fix the defects of the latter. An alternative strategy in which the parameters of the rigid base model are globally optimized along with the polarizability parameter is much more promising: the resulting 3-point polarizable model out-performs even the 5-point optimal rigid model by a large margin. We suggest that future development efforts consider 3- and 4-point polarizable models where global optimization of the "rigid base" is coupled to optimization of the polarizability to deliver globally optimal solns.
73. 73

    Shen, H.; Wu, Z.; Deng, M.; Wen, S.; Gao, C.; Li, S.; Wu, X. Molecular Dynamics Simulations of Ether- and Ester-Linked Phospholipid Bilayers: A Comparative Study of Water Models. J. Phys. Chem. B 2018, 122, 9399– 9408,  DOI: 10.1021/acs.jpcb.8b06726

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    73

    Molecular Dynamics Simulations of Ether- and Ester-Linked Phospholipid Bilayers: A Comparative Study of Water Models

    Shen, Hujun; Wu, Zhenhua; Deng, Mingsen; Wen, Shuiguo; Gao, Chenggui; Li, Shixiong; Wu, Xupu

    Journal of Physical Chemistry B (2018), 122 (40), 9399-9408CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Membrane Dipole potential influences a variety of important biol. processes involving cell membranes. Since it is quite challenging to directly measure the membrane dipole potential in expts., mol. dynamics (MD) simulation has emerged as a powerful tool for a reasonable prediction of the dipole potential. Although MD predictions agree well with expt. about the sign of dipole potential, the magnitude of dipole potential varies significantly with the force field parameters. It has been shown that the pos. dipole potential of PC bilayer membranes would be overestimated by a non-polarizable model owing to the treatment of many-body polarization effects in a mean-field fashion. In this work, we carried out atomistic MD simulations of the diphytanyl phosphatidylcholine (ether-DPhPC) and diphytanoyl phosphatidylcholine (ester-DPhPC) bilayers and made a comparative study of three different non-polarizable water models (TIP3P, TIP4P, and TIP5P). Interestingly, we discover that the calcd. dipole potential by the TIP5P model show a nice agreement with the result obtained using the cryoelectron microscopy (cryo-EM) expt., suggesting that a better description of electrostatic interactions in a non-polarizable water model can effectively ameliorate the overestimation in the calcn. of dipole potential. In addn., our MD results show that the substitution of the ether linkage for the ester linkage of phospholipid would bring about a change in the orientation of the linkage group with respect to the bilayer normal, leading to the difference in the membrane dipole potential. Surprisingly, although water mols. provide a major contribution to the pos. dipole potential, they have a limited impact on the difference of dipole potential between the ether-DPhPC and ester-DPhPC bilayer membranes.
74. 74

    Tempra, C.; Ollila, O. H. S.; Javanainen, M. Accurate Simulations of Lipid Monolayers Require a Water Model with Correct Surface Tension. J. Chem. Theory Comput. 2022, 18, 1862– 1869,  DOI: 10.1021/acs.jctc.1c00951

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    74

    Accurate Simulations of Lipid Monolayers Require a Water Model with Correct Surface Tension

    Tempra, Carmelo; Ollila, O. H. Samuli; Javanainen, Matti

    Journal of Chemical Theory and Computation (2022), 18 (3), 1862-1869CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Lipid monolayers provide our lungs and eyes their functionality and serve as proxy systems in biomembrane research. Therefore, lipid monolayers have been studied intensively including using mol. dynamics simulations, which are able to probe their lateral structure and interactions with, e.g., pharmaceuticals or nanoparticles. However, such simulations have struggled in describing the forces at the air-water interface. Particularly, the surface tension of water and long-range van der Waals interactions have been considered crit., but their importance in monolayer simulations has been evaluated only sep. Here, we combine the recent C36/LJ-PME lipid force field that includes long-range van der Waals forces with water models that reproduce exptl. surface tensions to elucidate the importance of these contributions in monolayer simulations. Our results suggest that a water model with correct surface tension is necessary to reproduce exptl. surface pressure-area isotherms and monolayer phase behavior. The latter includes the liq. expanded and liq. condensed phases, their coexistence, and the opening of pores at the correct area per lipid upon expansion. Despite these improvements of the C36/LJ-PME with certain water models, the std. cutoff-based CHARMM36 lipid model with the 4-point OPC water model still provides the best agreement with expts. Our results emphasize the importance of using high-quality water models in applications and parameter development in mol. dynamics simulations of biomols.
75. 75

    Klauda, J. B.; Kučerka, N.; Brooks, B. R.; Pastor, R. W.; Nagle, J. F. Simulation-based methods for interpreting x-ray data from lipid bilayers. Biophysical journal 2006, 90, 2796– 2807,  DOI: 10.1529/biophysj.105.075697

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    75

    Simulation-based methods for interpreting X-ray data from lipid bilayers

    Klauda, Jeffery B.; Kucerka, Norbert; Brooks, Bernard R.; Pastor, Richard W.; Nagle, John F.

    Biophysical Journal (2006), 90 (8), 2796-2807CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)

    The fully hydrated liq. cryst. phase of the dimyristoylphosphatidylcholine lipid bilayer at 30° was simulated using mol. dynamics with the CHARMM potential for five surface areas per lipid (A) in the range 55-65 Å2 that brackets the previously detd. exptl. area 60.6 Å2. The results of these simulations are used to develop a new hybrid zero-baseline structural model, denoted H2, for the electron d. profile, p(z), for the purpose of interpreting x-ray diffraction data. H2 and also the older hybrid baseline model were tested by fitting to partial information from the simulation and various constraints, both of which correspond to those available exptl. The A, ρ(z), and F(q) obtained from the models agree with those calcd. directly from simulation at each of the five areas, thereby validating this use of the models. The new H2 was then applied to exptl. dimyristoylphosphatidylcholine data; it yields A = 60.6 ± 0.5 Å2, in agreement with the earlier est. obtained using the hybrid baseline model. The electron d. profiles also compare well, despite considerable differences in the functional forms of the two models. Overall, the simulated ρ(z) at A = 60.7 Å2 agrees well with expt., demonstrating the accuracy of the CHARMM lipid force field; small discrepancies indicate targets for improvements. Lastly, a simulation-based model-free approach for obtaining A is proposed. It is based on interpolating the area that minimizes the difference between the exptl. F(q) and simulated F(q) evaluated for a range of surface areas. This approach is independent of structural models and could be used to det. structural properties of bilayers with different lipids, cholesterol, and peptides.
76. 76

    Buslaev, P.; Gordeliy, V.; Grudinin, S.; Gushchin, I. Principal component analysis of lipid molecule conformational changes in molecular dynamics simulations. J. Chem. Theory Comput. 2016, 12, 1019– 1028,  DOI: 10.1021/acs.jctc.5b01106

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    76

    Principal Component Analysis of Lipid Molecule Conformational Changes in Molecular Dynamics Simulations

    Buslaev, Pavel; Gordeliy, Valentin; Grudinin, Sergei; Gushchin, Ivan

    Journal of Chemical Theory and Computation (2016), 12 (3), 1019-1028CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Mol. dynamics simulations of lipid bilayers are ubiquitous nowadays. Usually, either global properties of the bilayer or some particular characteristics of each lipid mol. are evaluated in such simulations, but the structural properties of the mols. as a whole are rarely studied. Here, we show how a comprehensive quant. description of conformational space and dynamics of a single lipid mol. can be achieved via the principal component anal. (PCA). We illustrate the approach by analyzing and comparing simulations of DOPC bilayers obtained using eight different force fields: all-atom generalized AMBER, CHARMM27, CHARMM36, Lipid14, and Slipids and united-atom Berger, GROMOS43A1-S3, and GROMOS54A7. Similarly to proteins, most of the structural variance of a lipid mol. can be described by only a few principal components. These major components are similar in different simulations, although there are notable distinctions between the older and newer force fields and between the all-atom and united-atom force fields. The DOPC mols. in the simulations generally equilibrate on the time scales of tens to hundreds of nanoseconds. The equilibration is the slowest in the GAFF simulation and the fastest in the Slipids simulation. Somewhat unexpectedly, the equilibration in the united-atom force fields is generally slower than in the all-atom force fields. Overall, there is a clear sepn. between the more variable previous generation force fields and significantly more similar new generation force fields (CHARMM36, Lipid14, Slipids). We expect that the presented approaches will be useful for quant. anal. of conformations and dynamics of individual lipid mols. in other simulations of lipid bilayers.
77. 77

    Buslaev, P.; Mustafin, K.; Gushchin, I. Principal component analysis highlights the influence of temperature, curvature and cholesterol on conformational dynamics of lipids. Biochimica et Biophysica Acta (BBA)-Biomembranes 2020, 1862, 183253,  DOI: 10.1016/j.bbamem.2020.183253

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78. 78

    Michaud-Agrawal, N.; Denning, E. J.; Woolf, T. B.; Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. Journal of computational chemistry 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.
79. 79

    Gowers, R. J.; Linke, M.; Barnoud, J.; Reddy, T. J.; Melo, M. N.; Seyler, S. L.; Domanski, J.; Dotson, D. L.; Buchoux, S.; Kenney, I. M.; . MDAnalysis: a Python package for the rapid analysis of molecular dynamics simulations. Proceedings of the 15th python in Science Conference . July 11, 2016; p 105.

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80. 80

    Harris, C. R.; Millman, K. J.; van der Walt, S. J.; Gommers, R.; Virtanen, P.; Cournapeau, D.; Wieser, E.; Taylor, J.; Berg, S.; Smith, N. J.; Kern, R.; Picus, M.; Hoyer, S.; van Kerkwijk, M. H.; Brett, M.; Haldane, A.; del Río, J. F.; Wiebe, M.; Peterson, P.; Gérard-Marchant, P.; Sheppard, K.; Reddy, T.; Weckesser, W.; Abbasi, H.; Gohlke, C.; Oliphant, T. E. Array programming with NumPy. Nature 2020, 585, 357– 362,  DOI: 10.1038/s41586-020-2649-2

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    80

    Array programming with NumPy

    Harris, Charles R.; Millman, K. Jarrod; van der Walt, Stefan J.; Gommers, Ralf; Virtanen, Pauli; Cournapeau, David; Wieser, Eric; Taylor, Julian; Berg, Sebastian; Smith, Nathaniel J.; Kern, Robert; Picus, Matti; Hoyer, Stephan; van Kerkwijk, Marten H.; Brett, Matthew; Haldane, Allan; del Rio, Jaime Fernandez; Wiebe, Mark; Peterson, Pearu; Gerard-Marchant, Pierre; Sheppard, Kevin; Reddy, Tyler; Weckesser, Warren; Abbasi, Hameer; Gohlke, Christoph; Oliphant, Travis E.

    Nature (London, United Kingdom) (2020), 585 (7825), 357-362CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

    Abstr.: Array programming provides a powerful, compact and expressive syntax for accessing, manipulating and operating on data in vectors, matrixes and higher-dimensional arrays. NumPy is the primary array programming library for the Python language. It has an essential role in research anal. pipelines in fields as diverse as physics, chem., astronomy, geoscience, biol., psychol., materials science, engineering, finance and economics. For example, in astronomy, NumPy was an important part of the software stack used in the discovery of gravitational waves1 and in the first imaging of a black hole2. Here we review how a few fundamental array concepts lead to a simple and powerful programming paradigm for organizing, exploring and analyzing scientific data. NumPy is the foundation upon which the scientific Python ecosystem is constructed. It is so pervasive that several projects, targeting audiences with specialized needs, have developed their own NumPy-like interfaces and array objects. Owing to its central position in the ecosystem, NumPy increasingly acts as an interoperability layer between such array computation libraries and, together with its application programming interface (API), provides a flexible framework to support the next decade of scientific and industrial anal.
81. 81

    Kav, B. Pure POPC membrane simulations with the CHARMM- Drude force field (OpenMM 7.5.0). 2021;  DOI: 10.5281/zenodo.7607436 .

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82. 82

    Kav, B. OpenMM simulations of POPC using the CHARMM Drude2023 force field in xtc format. 2023;  DOI: 10.5281/zenodo.7916287 .

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83. 83

    Kav, B. Pure POPE membrane simulations with the CHARMM- Drude force field (OpenMM 7.5.0). 2021;  DOI: 10.5281/zenodo.7604627 .

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84. 84

    Kav, B. OpenMM simulations of POPE using the CHARMM Drude2023 force field in xtc format. 2023;  DOI: 10.5281/zenodo.7916494 .

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85. 85

    Kav, B. MD Simulation data for a pure POPE bilayer with AMOEBA force field + OpenMM. 2023;  DOI: 10.5281/zenodo.7622838 .

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86. 86

    Kav, B. Pure POPC Membrane with 350mM NaCl simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7586915 .

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87. 87

    Kav, B. Pure POPC Membrane with 450mM NaCl simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7591753 .

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88. 88

    Kav, B. Pure POPC Membrane with 650mM NaCl simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7596011 .

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89. 89

    Kav, B. Pure POPC Membrane with 1000mM NaCl simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7600326 .

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90. 90

    Kav, B. Pure POPC membrane simulations with 350 mM NaCl with the CHARMM-Drude2023 force field (OpenMM). 2023;  DOI: 10.5281/zenodo.8000095 .

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91. 91

    Kav, B. Pure POPC membrane simulations with 1000 mM NaCl with the CHARMM-Drude2023 force field (OpenMM). 2023;  DOI: 10.5281/zenodo.8000133 .

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92. 92

    Kav, B. Pure POPC Membrane with 350mM CaCl2 simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7600827 .

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93. 93

    Kav, B. Pure POPC Membrane with 450mM CaCl2 simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7605016 .

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94. 94

    Kav, B. Pure POPC Membrane with 650mM CaCl2 simulations using Drude Polarizable Force Field and OpenMM. 2020;  DOI: 10.5281/zenodo.7604040 .

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95. 95

    Kav, B. Pure POPC membrane simulations with 1000 mM CaCl2 with the CHARMM-Drude force field (OpenMM). 2023;  DOI: 10.5281/zenodo.7658975 .

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96. 96

    Kav, B. Pure POPC membrane simulations with 350 mM CaCl2 with the CHARMM-Drude2023 force field (OpenMM). 2023;  DOI: 10.5281/zenodo.8000065 .

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97. 97

    Kav, B. Pure POPC membrane simulations with 790 mM CaCl2 with the CHARMM-Drude2023 force field (OpenMM). 2023;  DOI: 10.5281/zenodo.7992137 .

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98. 98

    Kav, B. MD Simulation data for a pure DOPC bilayer without salt with AMOEBA force field + OpenMM. 2022;  DOI: 10.5281/zenodo.7604681 .

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99. 99

    Kav, B. MD Simulation data for a pure DOPC bilayer (450 mM NaCl) with AMOEBA force field + OpenMM. 2022;  DOI: 10.5281/zenodo.7604711 .

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100. 100

     Kav, B. MD Simulation data for a pure DOPC bilayer (1000 mM NaCl) with AMOEBA force field + OpenMM. 2023;  DOI: 10.5281/zenodo.7625844 .

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     There is no corresponding record for this reference.
101. 101

     Kav, B. MD Simulation data for a pure DOPC bilayer (450 mM CaCl2) with AMOEBA force field + OpenMM. 2022;  DOI: 10.5281/zenodo.7604842 .

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     There is no corresponding record for this reference.
102. 102

     Kav, B. MD Simulation data for a pure DOPC bilayer (1000 mM CaCl2) with AMOEBA force field + OpenMM. 2022;  DOI: 10.5281/zenodo.7604810 .

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103. 103

     Ollila, O. S.; Pabst, G. Atomistic resolution structure and dynamics of lipid bilayers in simulations and experiments. Biochim. Biophys. Acta 2016, 1858, 2512– 2528,  DOI: 10.1016/j.bbamem.2016.01.019

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     103

     Atomistic resolution structure and dynamics of lipid bilayers in simulations and experiments

     Ollila, O. H. Samuli; Pabst, Georg

     Biochimica et Biophysica Acta, Biomembranes (2016), 1858 (10), 2512-2528CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)

     Accurate details on the sampled atomistic resoln. structures of lipid bilayers can be exptl. obtained by measuring C-H bond order parameters, spin relaxation rates and scattering form factors. These parameters can be also directly calcd. from the classical atomistic resoln. mol. dynamics simulations (MD) and compared to the exptl. achieved results. This comparison measures the simulation model quality with respect to 'reality'. If agreement is sufficient, the simulation model gives an atomistic structural interpretation of the acquired exptl. data. Significant advance of MD models is made by jointly interpreting different expts. using the same structural model. Here the authors focus on phosphatidylcholine lipid bilayers, which out of all model membranes have been studied mostly by expts. and simulations, leading to the largest available dataset. From the applied comparisons the acyl chain region structure and rotational dynamics are generally well described in simulation models. Also changes with temp., dehydration and cholesterol concn. are qual. correctly reproduced. However, the quality of the underlying atomistic resoln. structural changes is uncertain. Even worse, when focusing on the lipid bilayer properties at the interfacial region, e.g. glycerol backbone and choline structures, and cation binding, many simulation models produce an inaccurate description of exptl. data. Thus extreme care must be applied when simulations are applied to understand phenomena where the interfacial region plays a significant role. This work is done by the NMRlipids Open Collaboration project running at https://nmrlipids.blogspot.fi and https://github.com/NMRLipids. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz R´og.
104. 104

     Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J. M.; Lu, C.; Dahlgren, M. K.; Mondal, S.; Chen, W.; Wang, L.; Abel, R.; Friesner, R. A.; Harder, E. D. OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules. J. Chem. Theory Comput. 2019, 15, 1863– 1874,  DOI: 10.1021/acs.jctc.8b01026

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     104

     OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules

     Roos, Katarina; Wu, Chuanjie; Damm, Wolfgang; Reboul, Mark; Stevenson, James M.; Lu, Chao; Dahlgren, Markus K.; Mondal, Sayan; Chen, Wei; Wang, Lingle; Abel, Robert; Friesner, Richard A.; Harder, Edward D.

     Journal of Chemical Theory and Computation (2019), 15 (3), 1863-1874CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

     Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chem. space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chem. specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small mol. conformational propensities, solvation, and protein-ligand binding.
105. 105

     Chandrasekhar, I.; Kastenholz, M.; Lins, R. D.; Oostenbrink, C.; Schuler, L. D.; Tieleman, D. P.; van Gunsteren, W. F. A consistent potential energy parameter set for lipids: dipalmitoylphosphatidylcholine as a benchmark of the GROMOS96 45A3 force field. Eur. Biophys. J. 2003, 32, 67– 77,  DOI: 10.1007/s00249-002-0269-4

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     105

     A consistent potential energy parameter set for lipids: dipalmitoylphosphatidylcholine as a benchmark of the GROMOS96 45A3 force field

     Chandrasekhar, Indira; Kastenholz, Mika; Lins, Roberto D.; Oostenbrink, Chris; Schuler, Lukas D.; Tieleman, D. Peter; van Gunsteren, Wilfred F.

     European Biophysics Journal (2003), 32 (1), 67-77CODEN: EBJOE8; ISSN:0175-7571. (Springer-Verlag)

     The performance of the GROMOS96 parameter set 45A3 developed for aliph. alkanes is tested on a bilayer of dipalmitoylphosphatidylcholine (DPPC) in water in the liq.-cryst. Lα phase. Variants of the force-field parameter set as well as different sets of simulation conditions or simulation parameter sets are evaluated. In the case of the force-field parameters, the van der Waals consts. for the non-bonded interaction of the ester carbonyl carbon and the partial charges and charge group definition of the phosphatidylcholine head group are examd. On the methodol. side, different cut-off distances for the non-bonded interactions, use of a reaction-field force due to long-range electrostatic interactions, the frequency of removal of the center of mass motion and the strength of the coupling of the pressure of the system to the pressure bath are tested. The area per lipid, as a measure of structure, the order parameters of the chain carbons, as a measure of membrane fluidity, and the translational diffusion of the lipids in the plane of the bilayer are calcd. and compared with exptl. values. An optimal set of simulation parameters for which the GROMOS96 parameter set 45A3 yields a head group area, chain order parameters and a lateral diffusion coeff. in accordance with the exptl. data is listed.
106. 106

     Kukol, A. Lipid Models for United-Atom Molecular Dynamics Simulations of Proteins. J. Chem. Theory Comput. 2009, 5, 615– 626,  DOI: 10.1021/ct8003468

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     106

     Lipid Models for United-Atom Molecular Dynamics Simulations of Proteins

     Kukol, Andreas

     Journal of Chemical Theory and Computation (2009), 5 (3), 615-626CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

     United-atom force fields for mol. dynamics (MD) simulations provide a higher computational efficiency, esp. in lipid membrane simulations, with little sacrifice in accuracy, when compared to all-atom force fields. Excellent united-atom lipid models are available, but in combination with depreciated protein force fields. In this work, a united-atom model of the lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine has been built with std. parameters of the force field GROMOS96 53a6 that reproduces the exptl. area per lipid of a lipid bilayer within 3% accuracy to a value of 0.623 ± 0.011 nm2 without the assumption of a const. surface area or the inclusion of surface pressure. In addn., the lateral self-diffusion const. and deuterium order parameters of the acyl chains are in agreement with exptl. data. Furthermore, models for 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) result in areas per lipid of 0.625 nm2 (DMPC), 0.693 nm2 (POPC), and 0.700 nm2 (POPG) from 40 ns MD simulations. Exptl. lateral self-diffusion coeffs. are reproduced satisfactorily by the simulation. The lipid models can form the basis for mol. dynamics simulations of membrane proteins with current and future versions of united-atom protein force fields.
107. 107

     Piggot, T. J.; Piñeiro, Á.; Khalid, S. Molecular Dynamics Simulations of Phosphatidylcholine Membranes: A Comparative Force Field Study. J. Chem. Theory Comput. 2012, 8, 4593– 4609,  DOI: 10.1021/ct3003157

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     107

     Molecular Dynamics Simulations of Phosphatidylcholine Membranes: A Comparative Force Field Study

     Piggot, Thomas J.; Pineiro, Angel; Khalid, Syma

     Journal of Chemical Theory and Computation (2012), 8 (11), 4593-4609CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

     Mol. dynamics simulations provide a route to studying the dynamics of lipid bilayers at atomistic or near atomistic resoln. Over the past 10 years or so, mol. dynamics simulations have become an established part of the biophysicist's tool kit for the study of model biol. membranes. As simulation time scales move from tens to hundreds of nanoseconds and beyond, it is timely to re-evaluate the accuracy of simulation models. A comparative anal. of five freely available force fields that are commonly used to model lipid bilayers is described. The anal. focuses on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. It is shown that some bilayer properties have a pronounced force field dependence, while others are less sensitive. In general, strengths and weaknesses are found, with respect to exptl. data, in all of the force fields studied. However, some combinations of simulation and force field parameters are found that should be avoided when simulating DPPC and POPC membranes. It is anticipated that the results presented for some of the membrane properties will guide future improvements for several force fields studied in this work.
108. 108

     Kučerka, N.; Nieh, M.-P.; Katsaras, J. Fluid phase lipid areas and bilayer thicknesses of commonly used phosphatidylcholines as a function of temperature. Biochimica et Biophysica Acta (BBA) -. Biomembranes 2011, 1808, 2761– 2771,  DOI: 10.1016/j.bbamem.2011.07.022

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109. 109

     Kučerka, N.; Nagle, J. F.; Sachs, J. N.; Feller, S. E.; Pencer, J.; Jackson, A.; Katsaras, J. Lipid Bilayer Structure Determined by the Simultaneous Analysis of Neutron and X-Ray Scattering Data. Biophys. J. 2008, 95, 2356– 2367,  DOI: 10.1529/biophysj.108.132662

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     109

     Lipid bilayer structure determined by the simultaneous analysis of neutron and X-ray scattering data

     Kucerka, Norbert; Nagle, John F.; Sachs, Jonathan N.; Feller, Scott E.; Pencer, Jeremy; Jackson, Andrew; Katsaras, John

     Biophysical Journal (2008), 95 (5), 2356-2367CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)

     Quant. structures were obtained for the fully hydrated fluid phases of dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC) bilayers by simultaneously analyzing x-ray and neutron scattering data. The neutron data for DOPC included two solvent contrasts, 50% and 100% D2O. For DPPC, addnl. contrast data were obtained with deuterated analogs DPPC_d62, DPPC_d13, and DPPC_d9. For the anal., we developed a model that is based on vol. probability distributions and their spatial conservation. The model's design was guided and tested by a DOPC mol. dynamics simulation. The model consistently captures the salient features found in both electron and neutron scattering d. profiles. A key result of the anal. is the mol. surface area, A. For DPPC at 50°C A = 63.0 Å2, whereas for DOPC at 30°C A = 67.4 Å2, with estd. uncertainties of 1 Å2. Although A for DPPC agrees with a recently reported value obtained solely from the anal. of x-ray scattering data, A for DOPC is almost 10% smaller. This improved method for detg. lipid areas helps to reconcile long-standing differences in the values of lipid areas obtained from stand-alone x-ray and neutron scattering expts. and poses new challenges for mol. dynamics simulations.
110. 110

     Rickeard, B. W.; Nguyen, M. H. L.; DiPasquale, M.; Yip, C. G.; Baker, H.; Heberle, F. A.; Zuo, X.; Kelley, E. G.; Nagao, M.; Marquardt, D. Transverse lipid organization dictates bending fluctuations in model plasma membranes. Nanoscale 2020, 12, 1438– 1447,  DOI: 10.1039/C9NR07977G

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     110

     Transverse lipid organization dictates bending fluctuations in model plasma membranes

     Rickeard, Brett W.; Nguyen, Michael H. L.; DiPasquale, Mitchell; Yip, Caesar G.; Baker, Hamilton; Heberle, Frederick A.; Zuo, Xiaobing; Kelley, Elizabeth G.; Nagao, Michihiro; Marquardt, Drew

     Nanoscale (2020), 12 (3), 1438-1447CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Membrane undulations play a vital role in many biol. processes, including the regulation of membrane protein activity. The asym. lipid compn. of most biol. membranes complicates theor. description of these bending fluctuations, yet exptl. data that would inform any such a theory is scarce. Here, we used neutron spin-echo (NSE) spectroscopy to measure the bending fluctuations of large unilamellar vesicles (LUV) having an asym. transbilayer distribution of high- and low-melting lipids. The asym. vesicles were prepd. using cyclodextrin-mediated lipid exchange, and were composed of an outer leaflet enriched in egg sphingomyelin (ESM) and an inner leaflet enriched in 1-palmitoyl-2-oleoyl-phosphoethanolamine (POPE), which have main transition temps. of 37°C and 25°C, resp. The overall membrane bending rigidity was measured at three temps.: 15°C, where both lipids are in a gel state; 45°C, where both lipids are in a fluid state; and 30°C, where there is gel-fluid co-existence. Remarkably, the dynamics for the fluid asym. LUVs (aLUVs) at 30°C and 45°C do not follow trends predicted by their sym. counterparts. At 30°C, compositional asymmetry suppressed the bending fluctuations, with the asym. bilayer exhibiting a larger bending modulus than that of sym. bilayers corresponding to either the outer or inner leaflet. We conclude that the compositional asymmetry and leaflet coupling influence the internal dissipation within the bilayer and result in membrane properties that cannot be directly predicted from corresponding sym. bilayers.
111. 111

     Ferreira, T. M.; Coreta-Gomes, F.; Ollila, O. H. S.; Moreno, M. J.; Vaz, W. L. C.; Topgaard, D. Cholesterol and POPC segmental order parameters in lipid membranes: solid state ¹H-¹³C NMR and MD simulation studies. Phys. Chem. Chem. Phys. 2013, 15, 1976– 1989,  DOI: 10.1039/C2CP42738A

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     111

     Cholesterol and POPC segmental order parameters in lipid membranes: solid state 1H-13C NMR and MD simulation studies

     Ferreira, Tiago Mendes; Coreta-Gomes, Filipe; Ollila, O. H. Samuli; Moreno, Maria Joao; Vaz, Winchil L. C.; Topgaard, Daniel

     Physical Chemistry Chemical Physics (2013), 15 (6), 1976-1989CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)

     The concn. of cholesterol in cell membranes affects membrane fluidity and thickness, and might regulate different processes such as the formation of lipid rafts. Since interpreting exptl. data from biol. membranes is rather intricate, investigations on simple models with biol. relevance are necessary to understand the natural systems. We study the effect of cholesterol on the mol. structure of multi-lamellar vesicles (MLVs) composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a phospholipid ubiquitous in cell membranes, with compns. in the range 0-60 mol% cholesterol. Order parameters, |SCH|, are exptl. detd. by using 1H-13C solid-state NMR (NMR) spectroscopy with segmental detail for all parts of both the cholesterol and POPC mols., namely the ring system and alkyl chain of the sterol, as well as the glycerol backbone, choline headgroup and the sn-1 and sn-2 acyl chains of POPC. With increasing cholesterol concn. the acyl chains gradually adopt a more extended conformation while the orientation and dynamics of the polar groups are rather unaffected. Addnl., we perform classical mol. dynamics simulations on virtual bilayers mimicking the POPC-cholesterol MLVs investigated by NMR. Good agreement between expts. and simulations is found for the cholesterol alignment in the bilayer and for the |SCH| profiles of acyl chains below 15 mol% cholesterol. Deviations occur for the choline headgroup and glycerol backbone parts of POPC, as well as for the phospholipid and cholesterol alkyl chains at higher cholesterol concns. The unprecedented detail of the NMR data enables a more complete comparison between simulations and expts. on POPC-cholesterol bilayers and may aid in developing more realistic model descriptions of biol. membranes.
112. 112

     Kučerka, N.; van Oosten, B.; Pan, J.; Heberle, F. A.; Harroun, T. A.; Katsaras, J. Molecular Structures of Fluid Phosphatidylethanolamine Bilayers Obtained from Simulation-to-Experiment Comparisons and Experimental Scattering Density Profiles. J. Phys. Chem. B 2015, 119, 1947– 1956,  DOI: 10.1021/jp511159q

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     113

     Molecular Structures of Fluid Phosphatidylethanolamine Bilayers Obtained from Simulation-to-Experiment Comparisons and Experimental Scattering Density Profiles

     Kucerka, Norbert; van Oosten, Brad; Pan, Jianjun; Heberle, Frederick A.; Harroun, Thad A.; Katsaras, John

     Journal of Physical Chemistry B (2015), 119 (5), 1947-1956CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

     Following our previous efforts in detg. the structures of commonly used PC, PG, and PS bilayers, we continue our studies of fully hydrated, fluid phase PE bilayers. The newly designed parsing scheme for PE bilayers was based on extensive MD simulations, and is utilized in the SDP anal. of both x-ray and neutron (contrast varied) scattering measurements. Obtained exptl. scattering form factors are directly compared to our simulation results, and can serve as a benchmark for future developed force fields. Among the evaluated structural parameters, namely, area per lipid A, overall bilayer thickness DB, and hydrocarbon region thickness 2DC, the PE bilayer response to changing temp. is similar to previously studied bilayers with different headgroups. On the other hand, the reduced hydration of PE headgroups, as well as the strong hydrogen bonding between PE headgroups, dramatically affects lateral packing within the bilayer. Despite sharing the same glycerol backbone, a markedly smaller area per lipid distinguishes PE from other bilayers (i.e., PC, PG, and PS) studied to date. Overall, our data are consistent with the notion that lipid headgroups govern bilayer packing, while hydrocarbon chains dominate the bilayer's response to temp. changes.
113. 113

     Ollila, S.; Hyvönen, M. T.; Vattulainen, I. Polyunsaturation in Lipid Membranes: Dynamic Properties and Lateral Pressure Profiles. J. Phys. Chem. B 2007, 111, 3139– 3150,  DOI: 10.1021/jp065424f

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     114

     Polyunsaturation in Lipid Membranes: Dynamic Properties and Lateral Pressure Profiles

     Ollila, Samuli; Hyvoenen, Marja T.; Vattulainen, Ilpo

     Journal of Physical Chemistry B (2007), 111 (12), 3139-3150CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)

     We elucidate the influence of unsatn. on single-component membrane properties, focusing on their dynamical aspects and lateral pressure profiles across the membrane. To this end, we employ atomistic mol. dynamics simulations to study five different membrane systems with varying degrees of unsatn., starting from satd. membranes and systematically increasing the level of unsatn., ending up with a bilayer of phospholipids contg. the docosahexaenoic acid. For an increasing level of unsatn., we find considerable effects on dynamical properties, such as accelerated dynamics of the phosphocholine head groups and glycerol backbones and speeded up rotational dynamics of the lipid mols. The lateral pressure profile is found to be altered by the degree of unsatn. For an increasing no. of double bonds, the peak in the middle of the bilayer decreases. This is compensated for by changes in the membrane-water interface region in terms of increasing peak heights of the lateral pressure profile. Implications of the findings are briefly discussed.
114. 114

     Li, Y.; Liu, Y.; Yang, B.; Li, G.; Chu, H. Polarizable atomic multipole-based force field for cholesterol. J. Biomol. Struct. Dyn. 2023, 0, 1– 11,  DOI: 10.1080/07391102.2023.2245045

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115. 115

     Ngo, V. A.; Fanning, J. K.; Noskov, S. Y. Comparative Analysis of Protein Hydration from MD simulations with Additive and Polarizable Force Fields. Advanced Theory and Simulations 2019, 2, 1800106,  DOI: 10.1002/adts.201800106

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116. 116

     Antila, H. S.; Wurl, A.; Ollila, O. S.; Miettinen, M. S.; Ferreira, T. M. Rotational decoupling between the hydrophilic and hydrophobic regions in lipid membranes. Biophys. J. 2022, 121, 68– 78,  DOI: 10.1016/j.bpj.2021.12.003

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     117

     Rotational decoupling between the hydrophilic and hydrophobic regions in lipid membranes

     Antila, Hanne S.; Wurl, Anika; Ollila, O. H. Samuli; Miettinen, Markus S.; Ferreira, Tiago M.

     Biophysical Journal (2022), 121 (1), 68-78CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

     Cells use homeostatic mechanisms to ensure an optimal compn. of distinct types of lipids in cellular membranes. The hydrophilic region of biol. lipid membranes is mainly composed of several types of phospholipid headgroups that interact with incoming mols., nanoparticles, and viruses, whereas the hydrophobic region consists of a distribution of acyl chains and sterols affecting membrane fluidity/rigidity related properties and forming an environment for membrane-bound mols. such as transmembrane proteins. A fundamental open question is to what extent the motions of these regions are coupled and, consequently, how strongly the interactions of phospholipid headgroups with other mols. depend on the properties and compn. of the membrane hydrophobic core. We combine advanced solid-state NMR spectroscopy with high-fidelity mol. dynamics simulations to demonstrate how the rotational dynamics of choline headgroups remain nearly unchanged (slightly faster) with incorporation of cholesterol into a phospholipid membrane, contrasting the well-known extreme slowdown of the other phospholipid segments. Notably, our results suggest a new paradigm in which phospholipid dipole headgroups interact as quasi-freely rotating flexible dipoles at the interface, independent of the properties in the hydrophobic region.
117. 117

     Klauda, J. B.; Roberts, M. F.; Redfield, A. G.; Brooks, B. R.; Pastor, R. W. Rotation of Lipids in Membranes: Molecular Dynamics Simulation, 31P Spin-Lattice Relaxation, and Rigid-Body Dynamics. Biophys. J. 2008, 94, 3074– 3083,  DOI: 10.1529/biophysj.107.121806

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     118

     Rotation of lipids in membranes: molecular dynamics simulation, 31P spin-lattice relaxation, and rigid-body dynamics

     Klauda, Jeffery B.; Roberts, Mary F.; Redfield, Alfred G.; Brooks, Bernard R.; Pastor, Richard W.

     Biophysical Journal (2008), 94 (8), 3074-3083CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)

     Mol. dynamics simulations and 31P-NMR spin-lattice (R1) relaxation rates from 0.022 to 21.1 T of fluid phase dipalmitoylphosphatidylcholine bilayers are compared. Agreement between expt. and direct prediction from simulation indicates that the dominant slow relaxation (correlation) times of the dipolar and chem. shift anisotropy spin-lattice relaxation are ∼10 ns and 3 ns, resp. Overall reorientation of the lipid body, consisting of the phosphorus, glycerol, and acyl chains, is well described within a rigid-body model. Wobble, with D.perp. = 1-2×108 s-1, is the primary component of the 10 ns relaxation; this timescale is consistent with the tumbling of a lipid-sized cylinder in a medium with the viscosity of liq. hexadecane. The value for D‖, the diffusion const. for rotation about the long axis of the lipid body, is difficult to det. precisely because of averaging by fast motions and wobble; it is tentatively estd. to be 1×107 s-1. The resulting D‖/D.perp. ≈ 0.1 implies that axial rotation is strongly modulated by interactions at the lipid/water interface. Rigid-body modeling and potential of mean force evaluations show that the choline group is relatively uncoupled from the rest of the lipid. This is consistent with the ratio of chem. shift anisotropy and dipolar correlation times reported here and the previous observations that 31P-NMR lineshapes are axially sym. even in the gel phase of dipalmitoylphosphatidylcholine.
118. 118

     Jämbeck, J. P. M.; Lyubartsev, A. P. An Extension and Further Validation of an All-Atomistic Force Field for Biological Membranes. J. Chem. Theory Comput. 2012, 8, 2938– 2948,  DOI: 10.1021/ct300342n

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     119

     An Extension and Further Validation of an All-Atomistic Force Field for Biological Membranes

     Jambeck Joakim P M; Lyubartsev Alexander P

     Journal of chemical theory and computation (2012), 8 (8), 2938-48 ISSN:1549-9618.

     Biological membranes are versatile in composition and host intriguing molecular processes. In order to be able to study these systems, an accurate model Hamiltonian or force field (FF) is a necessity. Here, we report the results of our extension of earlier developed all-atomistic FF parameters for fully saturated phospholipids that complements an earlier parameter set for saturated phosphatidylcholine lipids (J. Phys. Chem. B, 2012, 116, 3164-3179). The FF, coined Slipids (Stockholm lipids), now also includes parameters for unsaturated phosphatidylcholine and phosphatidylethanolamine lipids, e.g., POPC, DOPC, SOPC, POPE, and DOPE. As the extended set of parameters is derived with the same philosophy as previously applied, the resulting FF has been developed in a fully consistent manner. The capabilities of Slipids are demonstrated by performing long simulations without applying any surface tension and using the correct isothermal-isobaric (NPT) ensemble for a range of temperatures and carefully comparing a number of properties with experimental findings. Results show that several structural properties are very well reproduced, such as scattering form factors, NMR order parameters, thicknesses, and area per lipid. Thermal dependencies of different thicknesses and area per lipid are reproduced as well. Lipid diffusion is systematically slightly underestimated, whereas the normalized lipid diffusion follows the experimental trends. This is believed to be due to the lack of collective movement in the relatively small bilayer patches used. Furthermore, the compatibility with amino acid FFs from the AMBER family is tested in explicit transmembrane complexes of the WALP23 peptide with DLPC and DOPC bilayers, and this shows that Slipids can be used to study more complex and biologically relevant systems.
119. 119

     Seelig, J.; MacDonald, P. M.; Scherer, P. G. Phospholipid head groups as sensors of electric charge in membranes. Biochemistry 1987, 26, 7535– 7541,  DOI: 10.1021/bi00398a001

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     120

     Phospholipid head groups as sensors of electric charge in membranes

     Seelig, Joachim; MacDonald, Peter M.; Scherer, Peter G.

     Biochemistry (1987), 26 (24), 7535-41CODEN: BICHAW; ISSN:0006-2960.

     Phospholipid head groups are shown to function as sensors of the elec. charge at the membrane surface. The phosphatidylcholine head group conformation was shown by 2H NMR to be sensitive to the elec. surface charge, with pos. charges causing changes inverse to those caused by neg. charges. The quadrupole splitting varied linearly with surface charge at .ltorsim.70 mC/m2. Charge was modified by addn. of such agents as quaternary ammonium salts, dialkylphosphates, local anesthetics, neg. charged phospholipids, tetraphenylphosphonium, or tetraphenylborate. Recent results on the conformation, orientation, and dynamics of lipid polar groups in crystals and in membranes are reviewed, and practical and theor. consequences of the sensitivity of head group conformation to membrane surface charge are discussed.
120. 120

     Venable, R. M.; Luo, Y.; Gawrisch, K.; Roux, B.; Pastor, R. W. Simulations of Anionic Lipid Membranes: Development of Interaction-Specific Ion Parameters and Validation Using NMR Data. J. Phys. Chem. B 2013, 117, 10183– 10192,  DOI: 10.1021/jp401512z

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     121

     Simulations of Anionic Lipid Membranes: Development of Interaction-Specific Ion Parameters and Validation Using NMR Data

     Venable, Richard M.; Luo, Yun; Gawrisch, Klaus; Roux, Benoit; Pastor, Richard W.

     Journal of Physical Chemistry B (2013), 117 (35), 10183-10192CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

     Overbinding of ions to lipid head groups is a potentially serious artifact in simulations of charged lipid bilayers. In this study, the Lennard-Jones radii in the CHARMM force field for interactions of Na+ and lipid oxygen atoms of carboxyl, phosphate, and ester groups were revised to match osmotic pressure data on sodium acetate and electrophoresis data on palmitoyloleoyl phosphatidylcholine (POPC) vesicles. The new parameters were then validated by successfully reproducing previously published exptl. NMR deuterium order parameters for dimyristoyl phosphatidylglycerol (DMPG) and newly obtained values for palmitoyloleoyl phosphatidylserine (POPS). Although the increases in Lennard-Jones diams. are only 0.02-0.12 Å, they are sufficient to reduce Na+ binding, and thereby increase surface areas per lipid by 5-10% compared with the unmodified parameters.
121. 121

     Han, K.; Venable, R. M.; Bryant, A.-M.; Legacy, C. J.; Shen, R.; Li, H.; Roux, B.; Gericke, A.; Pastor, R. W. Graph–Theoretic Analysis of Monomethyl Phosphate Clustering in Ionic Solutions. J. Phys. Chem. B 2018, 122, 1484– 1494,  DOI: 10.1021/acs.jpcb.7b10730

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     122

     Graph-Theoretic Analysis of Monomethyl Phosphate Clustering in Ionic Solutions

     Han, Kyungreem; Venable, Richard M.; Bryant, Anne-Marie; Legacy, Christopher J.; Shen, Rong; Li, Hui; Roux, Benoit; Gericke, Arne; Pastor, Richard W.

     Journal of Physical Chemistry B (2018), 122 (4), 1484-1494CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

     All-atom mol. dynamics simulations combined with graph-theoretic anal. reveal that clustering of the monomethyl phosphate dianion (MMP2-) was strongly influenced by the types and combinations of cations in the soln. While Ca2+ promoted formation of stable and large MMP2- clusters, K+ alone did not. Nonetheless, clusters were larger and their link lifetimes were longer in mixts. of K+ and Ca2+. This "synergistic" effect depends sensitively on the Lennard-Jones interaction parameters between Ca2+ and the phosphorus oxygen, and correlated with the hydration of clusters. The pronounced MMP2- clustering effect of Ca2+ in the presence of K+ was confirmed by FTIR spectroscopy. The characterization of the cation-dependent clustering of MMP2- provided a starting point for understanding cation-dependent clustering of phosphoinositides in cell membranes.
122. 122

     Ollila, S. MD simulation trajectory and related files for POPC bilayer with 350mM NaCl (CHARMM36, Gromacs 4.5). 2015;  DOI: 10.5281/zenodo.32496 .

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123. 123

     Ollila, S. MD simulation trajectory and related files for POPC bilayer with 690mM NaCl (CHARMM36, Gromacs 4.5). 2015;  DOI: 10.5281/zenodo.32497 .

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124. 124

     Ollila, S. MD simulation trajectory and related files for POPC bilayer with 950mM NaCl (CHARMM36, Gromacs 4.5). 2015;  DOI: 10.5281/zenodo.32498 .

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125. 125

     Nencini, R. CHARMM36, NB-Fix approaches, without NBFIX, POPC membrane, Ca, Na ions,. 2019;  DOI: 10.5281/zenodo.3434396 .

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126. 126

     Melcr, J. Simulations of POPC lipid bilayer in water solution at various NaCl, KCl and CaCl2 concentrations using ECC-POPC force field. 2017;  DOI: 10.5281/zenodo.3335503 .

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127. 127

     Akutsu, H.; Seelig, J. Interaction of metal ions with phosphatidylcholine bilayer membranes. Biochemistry 1981, 20, 7366– 7373,  DOI: 10.1021/bi00529a007

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     128

     Interaction of metal ions with phosphatidylcholine bilayer membranes

     Akutsu, Hideo; Seelig, Joachim

     Biochemistry (1981), 20 (26), 7366-73CODEN: BICHAW; ISSN:0006-2960.

     The interaction of mono-, di-, and trivalent metal ions with bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was investigated with 2H and 31P magnetic resonance. With selectively deuterated lipids, the measurements of the residual 2H quadrupole splitting provided a sensitive handle to monitor directly the binding of ions, including the weak binding of Na+ or (CH3)4N+. For the α segment of the choline group (-NCH2CD2O-) changes in the quadrupole splitting of ≤9 kHz were obsd. All measurements were made with nonsonicated DPPC dispersions. The ion concns. were varied between 5 mM and 2M, an almost 50-fold larger concn. range than accessible with NMR shift reagents. From a systematic comparison of various ions, the following conclusions were derived. (1) Addn. of metal ions led to a structural change at the level of the polar groups. The glycerol backbone or the beginning of the fatty acyl chains was not affected. (2) The strength of interaction increased with the charge of the metal ion in the order Na+ < Ca2+ < La3+. However, distinct differences were also noted between ions of the same charge. Furthermore, the strongly hydrophobic (Ph)4N+ induced almost the same change as La3+. (3) The variation of the quadrupole splittings with ion concn. exhibited a plateau value at high concns. of La3+. The titrn. curves of DPPC with Ca2+ and La3+ could be described in terms of a Langmuir adsorption isotherm with an interaction potential. Apparent binding consts. of KLa3+ = ∼120 M-1 and KCa2+ = ∼19 M-1 were derived. (4) The addn. of NaCl considerably enhanced the binding of Ca2+ and La3+, apparently without affecting the plateau value of the quadrupole splitting. (5) The ion-induced conformational changes were qual. similar for all ions investigated. The various binding data could be summarized by plotting the quadrupole splittings of the α segment (-OCD2CH2N-) vs. those of the β position (-OCH2CD2N-). This plot yielded a straight line comprising all ions and concns. investigated except Eu3+. The quadrupole splittings of DPPC obsd. in the presence of CHCl3 or cholesterol and the variation of the quadrupole splittings with temp. could also be summarized in a linear plot that was different from that obtained for metal ion binding. This suggests that existence of ≥2 kinds of structural responses of the polar head groups to external perturbations.
128. 128

     Altenbach, C.; Seelig, J. Calcium binding to phosphatidylcholine bilayers as studied by deuterium magnetic resonance. Evidence for the formation of a calcium complex with two phospholipid molecules. Biochemistry 1984, 23, 3913– 3920,  DOI: 10.1021/bi00312a019

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     129

     Calcium binding to phosphatidylcholine bilayers as studied by deuterium magnetic resonance. Evidence for the formation of a calcium complex with two phospholipid molecules

     Altenbach, Christian; Seelig, Joachim

     Biochemistry (1984), 23 (17), 3913-20CODEN: BICHAW; ISSN:0006-2960.

     The binding of Ca2+ to bilayer membranes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) was investigated with at. absorption spectroscopy and 2H MMR. At. absorption spectroscopy allowed the detn. of the amt. of Ca2+ bound to the membrane surface (Cb) at low Ca2+ concns. (3-100 mM). Simultaneous measurements of the 2H NMR spectra of POPC with specifically deuterated choline head groups revealed a linear relation between the quadrupole splitting and the amt. of bound Ca2+. With this calibration, the amt. of bound Ca2+ could be detd. from the 2H spectra under conditions where at. absorption spectroscopy was tech. not feasible, i.e., in the concn. range 0.1-5M CaCl2. The Ca2+ binding isotherm exhibited satn. behavior. The quadrupole splitting at the satn. limit corresponded to the binding stoichiometry of 1 Ca2+/2 POPC mols. The surface charge d. (σ) could be evaluated from the amt. of bound Ca2+ and the surface area/POPC mol. By employing the Gouy-Chapman theory, it was then possible to det. the surface potential and the Ca2+ concn. immediately at the lipid-water interface (CI). With this set of exptl. parameters, various models for the mode of Ca2+ binding were tested. A simple partition equil. or a Langmuir adsorption model could be ruled out. However, a very good fit to the exptl. data was obtained by applying the law of mass action in the form Cb/(1 - 2Cb)2 = KCI in which K is the only adjustable parameter. This model independently supports the above conclusion of a Ca2+-to-phospholipid stoichiometry of 1:2. For POPC in the liq.-cryst. state, this model predicts Ca2+ binding consts. of K = 13.8 M-1 (0.1M NaCl, 25%) and 7.0 M-1 (no NaCl, 40°).
129. 129

     Kav, B.; Strodel, B. Does the inclusion of electronic polarisability lead to a better modelling of peptide aggregation?. RSC Adv. 2022, 12, 20829– 20837,  DOI: 10.1039/D2RA01478E

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130. 130

     Shayestehpour, O.; Zahn, S. Ion Correlation in Choline Chloride–Urea Deep Eutectic Solvent (Reline) from Polarizable Molecular Dynamics Simulations. J. Phys. Chem. B 2022, 126, 3439– 3449,  DOI: 10.1021/acs.jpcb.1c10671

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     131

     Ion Correlation in Choline Chloride-Urea Deep Eutectic Solvent (Reline) from Polarizable Molecular Dynamics Simulations

     Shayestehpour, Omid; Zahn, Stefan

     Journal of Physical Chemistry B (2022), 126 (18), 3439-3449CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

     In recent years, deep eutectic solvents (DESs) emerged as highly tunable and environmentally friendly alternatives to common ionic liqs. and org. solvents. In this work, a polarizable model based on the CHARMM Drude polarizable force field is developed for a 1:2 ratio mixt. of choline chloride/urea (reline) DES. To successfully reproduce the structure of the liq. as compared to first-principles mol. dynamics simulations, a damping factor was introduced to correct the obsd. over-binding between the chloride and the hydrogen bonding site of choline. Investigated radial distributions reveal the formation of hydrogen bonds between all the constituents of reline and similar interactions for chloride and urea's oxygen atoms, which could contribute to the m.p. depression of the mixt. Predicted dynamic properties from our polarizable force field are in good agreement with expts., showing significant improvements over nonpolarizable models. Similar to some ionic liqs., an oscillatory behavior in the velocity autocorrelation function of the anion is visible, which can be interpreted as a rattling motion of the lighter anion surrounded by the heavier cations. The obtained results for ionic cond. of reline show some degree of correlated ion motion in this DES. However, a joint diffusion of ion pairs cannot be obsd. during the simulations.