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Impact of Thiol–Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor

Sanchita Hati
Sanchita Hati
Department of Chemistry, University of Wisconsin—Eau Claire, Eau Claire, Wisconsin 54701, United States
More by Sanchita Hati
and
Sudeep Bhattacharyya*
Sudeep Bhattacharyya
Department of Chemistry, University of Wisconsin—Eau Claire, Eau Claire, Wisconsin 54701, United States
*Email: [email protected]
More by Sudeep Bhattacharyya
http://orcid.org/0000-0002-3960-1239

Cite this: ACS Omega 2020, 5, 26, 16292–16298

Publication Date (Web):June 23, 2020

https://doi.org/10.1021/acsomega.0c02125

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Abstract

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease (COVID-19), which started in 2019. This is a member of Coronaviridae family in the genus Betacoronavirus, which also includes SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV and SARS-CoV-2 to enter the host cells. In particular, the interaction of viral spike proteins with ACE2 is a critical step in the viral replication cycle. The receptor-binding domain of the viral spike proteins and ACE2 have several cysteine residues. In this study, the role of thiol–disulfide balance on the interactions between SARS-CoV/CoV-2 spike proteins and ACE2 was investigated using molecular dynamics simulations. The study revealed that the binding affinity was significantly impaired when all of the disulfide bonds of both ACE2 and SARS-CoV/CoV-2 spike proteins were reduced to thiol groups. The impact on the binding affinity was less severe when the disulfide bridges of only one of the binding partners were reduced to thiols. This computational finding possibly provides a molecular basis for the differential COVID-19 cellular recognition due to the oxidative stress.

1. Introduction

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The novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or simply COVID-19 is the seventh member of the coronavirus family. (1) The other two viruses in this family that infect humans are severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). These are positive-sense, single-strand enveloped RNA viruses. The coronavirus particles contain four main structural proteins: the spike, membrane, envelope, and nucleocapsid. (1,2) The spike protein protrudes from the envelope of the virion and consists of two subunits: a receptor-binding domain (RBD) that interacts with the receptor proteins of host cells and a second subunit that facilitates fusion of the viral membrane into the host cell membrane. Recent studies showed that the RBD of spike proteins of SARS-CoV and SARS-CoV-2 interact with angiotensin-converting enzyme 2 (ACE2). ACE2 belongs to the membrane-bound carboxydipeptidase family. It is attached to the outer surfaces of cells and is widely distributed in the human body. In particular, higher expression of ACE2 is observed in organs such as small intestine, colon, kidney, and heart, while ACE2 expression is comparatively lower in the liver and lungs. (3,4)

The role of oxidative stress on the binding of viral proteins on the host cell surface receptors is a relatively underexplored area of biomedical research. (5−10) Previous studies have indicated that the entry of viral glycoprotein is impacted by thiol–disulfide balance on the cell surface. (5,7−9,11,12) Any perturbations in the thiol−disulfide equilibrium are also found to deter the entry of viruses into their target cells. (5) The first step of the viral entry involves binding of the viral envelop protein onto a cellular receptor. This is followed by endocytosis, after which conformational changes of the viral protein help the induction of the viral protein into the endosomal membrane, finally releasing the viral content into the cell. These conformational changes are mediated by pH changes as well as the conversion of disulfide into the thiol group of the viral spike protein. (7) Several cell surface oxidoreductases (9) regulate the thiol–disulfide exchange, responsible for conformational changes of viral proteins needed for virus entry into host cells.

In the backdrop of a significant mortality rate for SARS-CoV-2 (hereinafter referred to as CoV-2) infection, it is important to know if the thiol–disulfide balance plays any role in the binding of the spike glycoprotein onto the host cell receptor protein ACE2. A recent study with the spike glycoprotein of SARS-CoV (hereinafter referred to as CoV) has exhibited a complete redox insensitivity; (7) despite the reduction of all disulfide bridges of CoV to thiols, its binding to ACE2 remained unchanged. (7) However, this study did not probe the redox sensitivity of the ACE2 receptor. Thus, in the present study, we computationally investigated the redox state of both partners (ACE2 and CoV/CoV-2) on their binding affinities. The structure of CoV (13) and CoV-2 (14,15) complexed with ACE2 are known, and the noncovalent interactions at the protein–protein interface (16) have been reported recently. Using these reported structures, molecular dynamics simulations and electrostatic field calculations were performed to explore the impact of thiol–disulfide balance on CoV/CoV-2 and ACE2 binding affinities. The structural and dynamical changes due to the alteration in the redox states of cysteines in the interacting proteins were analyzed, and their effects on binding free energies were studied.

2. Results and Discussion

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The molecular basis of the binding of spike proteins to ACE2 is known from X-ray crystallographic (SARS-CoV) (13) and cryo-electron microscopic (SARS-CoV-2) (16) studies. The sequence alignment of CoV and CoV-2 spike proteins showed a high sequence identity (>75%), indicating that their binding to ACE2 receptors will be similar (Figure 1). In both bound structures, the RBD of CoV and CoV-2 is found to be complexed with ACE2 (Figure 2). Both ACE2 and CoV-2 possess four disulfide bridges, whereas the CoV subunit has only two disulfide linkages (Table 1 and Figure 2a,b). Two large helices of ACE2 form a curved surface (Figure 2, illustrated by the dashed curved line) that interacts with the concave region of CoV or CoV-2 subunit.

Figure 1. Sequence alignment (generated by Clustal Omega (35)) between the receptor-binding domain of SARS-CoV and SARS-CoV-2 proteins. “*” represents the identical residues, “:” and “.” represent strongly and weakly similar residues, respectively, and gap represents dissimilar residues. The cysteine residues are highlighted in yellow.

Figure 2. Structures of protein complexes: (a) SARS-CoV···ACE2 and (b) SARS-CoV-2···ACE2. All of the disulfide bridges between cysteine residues are shown in green van der Waals (vdW) spheres and thiol groups in cyan licorice.

Table 1. Sequences of the Receptor-Binding Domain of SARS-CoV and SARS-CoV-2 Proteins^a

^{^a}

The cysteine residues are highlighted in yellow and disulfide bonds are shown using black solid lines. The start and end residues in the crystal structures are numbered and highlighted in red. The gray highlighted residues are missing in the crystal structure.

2.1. Structural Changes along the Trajectory

In all cases, the simulation started with an equilibrated structure that was obtained after minimizing the neutralized solvated protein complex built from the experimentally determined structures. The evolution of the protein structure along the molecular dynamics (MD) trajectory was monitored by calculating the root-mean-square deviation (RMSD) of each structure from the starting structure as a frame of reference following the standard procedure. (17) Briefly, during the MD simulation, the protein coordinates were recorded for every 10 ps interval and an RMSD of each frame was calculated from the average root-mean-square displacement of backbone C_α atoms with respect to the initial structure. Then, the RMSD values, averaged over conformations stored during 1 ns time, were plotted against the simulated time (Figure 3). Compared to the starting structure, only a moderate backbone fluctuation was noted in all protein complexes during 20 ns simulations, and the maximum of RMSD was in the range of 2.0–3.8 Å (Table 2). The evolution of dynamics was smooth, and its stability was demonstrated by the standard deviation of the computed RMSDs, which was less than 0.3 Å. Taken together, the results of the simulations showed no unexpected structural deformation of the SARS-CoV/CoV-2···ACE2 complex in both, reduced (thiol groups) and oxidized (disulfide bonds) states (Table 2).

Figure 3. RMSDs, averaged over 1 ns MD simulation, of the protein complexes of ACE2 and SARS-CoV or SARS-CoV-2. Disulfide-containing proteins are referred to as oxidized with a shorthand notation of “ox”, while thiol variants are denoted with “red” notation.

Table 2. Evolution of the Structure of the Protein Complexes for the Oxidized and Reduced Variants Observed during 20 ns Molecular Dynamics Simulations^a

protein systems	number of disulfide moieties remaining	disulfide bridges present	RMSD (Å)	fluctuation (Å)
CoV^ox···ACE2^ox	6	CoV: C366:::C419, C467:::C474, ACE2: C133:::C141, C344:::C361, C366:::C419, C530:::C542	2.0	0.2
CoV^red···ACE2^ox	4	ACE2: C133:::C141, C344:::C361, C366:::C419, C530:::C542	3.8	0.3
CoV^ox···ACE2^red	2	CoV: C366:::C419, C467:::C474	3.1	0.3
CoV^red···ACE2^red	0	none	3.6	0.2
CoV-2^ox···ACE2^ox	8	CoV-2: C336:::C361, C379:::C432, C391:::C525, C480:::C488, ACE2: C133:::C141, C344:::C361, C366:::C419, C530:::C542
CoV-2^red···ACE2^ox	4	ACE2: C133:::C141, C344:::C361, C366:::C419, C530:::C542	2.7	0.2
CoV-2^ox···ACE2^red	4	CoV-2: C336:::C361, C379:::C432, C391:::C525, C480:::C488	2.8	0.2
CoV-2^red···ACE2^red	0	none	3.1	0.2

^{^a}

For each protein system, the “RMSD” column contains the average of the last 5 ns RMSD, and the “fluctuation” column represents the standard deviation computed based on the starting structure as a reference.

2.2. Thermal Fluctuations due to the Cleavage of Disulfide Bridges

The MD simulation results indicated that the flexibility of different structural elements of the interacting proteins altered upon the cleavage of disulfide bridges (oxidized state) producing sulfydryl (thiol) groups (reduced state). For each complex, the impact of the reduction of the disulfide bridges was probed by calculating residue-level root-mean-square fluctuations (RMSF) of C_α atoms with respect to the average structure from its MD simulation trajectory. Changes in the backbone flexibility due to complete reduction of all disulfides to thiols of both interacting proteins are shown in Figure 4a,b, where the backbone is color-coded to indicate the magnitude of thermal fluctuations. Larger and smaller backbone fluctuations are shown in red and blue, respectively, whereas the medium fluctuation regions are shown in green. The backbone fluctuation analysis demonstrated that the cleavage of disulfide bridges indeed affected the flexibility of the local regions as they became more dynamic (Figure 4b). A significant alteration in backbone flexibility was noticed at the interface of CoV and ACE2 subunits when both proteins are in the fully reduced states, i.e., all disulfides are changed to sulfydryl groups. As it is evident from Figure 4b, the helix (residues 52–64) of ACE2 became very mobile, due to the rupture of the nearby C344:::C361 disulfide. The second region belongs to the flexible loop consisting of residues 463–474 of the CoV subunit (residues 478–489 of the CoV-2 subunit), which interacts with the N-terminal segment of the ACE2. The cleavage of the disulfides C467:::C474 in CoV and C480:::C488 in CoV-2 resulted in higher thermal fluctuation.

Figure 4. Change in residue-level RMSFs of C_α atoms in the oxidized and reduced protein complexes: (a) SARS-CoV···ACE2 and (b) SARS-CoV-2···ACE2. The cysteine residues, for each protein system (labeled in Figure 2), are highlighted as vdW spheres. The backbone as well as the cysteine residues are color-coded, large fluctuations are shown in red, and small fluctuations are in blue. The medium-scale fluctuations are shown in green.

2.3. Binding Study

The computed Gibbs binding free energy (Δ_bindG°) of protein complexes (Table 3) demonstrated that the binding of CoV or CoV-2 with ACE2 occurs because the attractive electrostatic interactions between the individual subunits prevail over the desolvation due to the complexation. The complex formation results in desolvation from proteins’ surfaces at the protein–protein interface, thereby producing a positive ΔΔ_solvG_corr for all protein systems (Table 3). For the formation of a stable protein–protein complex, this energy has to be counterbalanced by the negative electrostatic interactions, Δ_CoulG, between the interacting proteins.

Table 3. Various Components of the Gibbs Free Energy of Binding Calculated by Implicit Solvation and Adaptive-Basis Poisson–Boltzmann Solver (APBS)^a

protein systems	Coulombic interaction free energy Δ_CoulG	corrected solvation free energy difference ΔΔ_solvG_corr	Gibbs free energy of binding Δ_bindG°
CoV^ox···ACE2^ox	–564.5	557.2	–7.3^b
CoV^red···ACE2^ox	–673.0	661.8	–11.2
CoV^ox···ACE2^red	–696.6	693.1	–3.4
CoV^red···ACE2^red	–528.4	580.4	52.0
CoV-2^ox···ACE2^ox	–659.6	648.2	–10.4^c
CoV-2^red···ACE2^ox	–638.2	632.2	–6.0
CoV-2^ox···ACE2^red	–531.9	528.1	–3.8
CoV-2^red···ACE2^red	–655.3	712.6	57.3

^{^a}

All energies are expressed in kcal/mol. An estimated uncertainty of 1–3 kcal/mol was determined for the computed Gibbs free energy.

^{^b}

An experimental value of −10.3 kcal/mol was obtained for SARS-CoV by Lan et al. (34)

^{^c}

An experimental K_d value of −10.4 kcal/mol for SARS-CoV-2···ACE2 complex, reported by Wang et al., (15) was used as correction in eq 3.

When the disulfides of the RBD of CoV and CoV-2 were reduced to thiols, the impact of reduction on the binding of these two proteins with ACE2 was different. The computed Δ_bindG° for CoV^ox···ACE2^ox and CoV^red···ACE2^ox are −7.3 and −11.2 kcal/mol, respectively (Table 3), indicating a slightly tighter binding of the reduced CoV RBD to ACE2. The experimentally known K_d value for the CoV^ox···ACE2^ox system is 325 nM, (14) which corresponds to a Δ_bindG° value of −8.9 kcal/mol. Therefore, the computationally determined Δ_bindG° for CoV^ox···ACE2^ox binding is comparable to the experimental value. Although there is no experimentally determined K_d available for the CoV^red···ACE2^ox system, the binding assay with CoV^red RBD was found to have no redox sensitivity for its binding to ACE2. (7) The small favorability of CoV^red···ACE2^ox binding, as observed from the computation, indicates that the reduction of CoV did not have much impact on its binding affinity for ACE2 and could explain the experimentally observed redox insensitivity. (7) In the case of CoV-2, its binding with ACE2 became less favorable when all of the disulfides of RBD were reduced to thiols. The computed Gibbs binding free energies were increased by ∼4.5 kcal/mol for the reduced CoV-2; Δ_bindG^o of CoV-2^ox···ACE2^ox and CoV-2^red···ACE2^ox are −10.4 and −6.0 kcal/mol, respectively.

In contrast, the reduction of disulfides of ACE2 impaired the binding significantly for both CoV and CoV-2 proteins. The Gibbs binding free energies of viral spike proteins CoV and CoV-2 with ACE2^red, namely, CoV^ox···ACE2^red and CoV-2^ox···ACE2^red are −3.4 and −3.8 kcal/mol, respectively. These Δ_bindG° values are ∼4 to 6 kcal/mol more positive than what were observed for the oxidized forms of ACE2 (i.e., CoV^ox···ACE2^ox and CoV-2^ox···ACE2^ox in Table 3). However, when all disulfides in CoV/CoV-2 as well as ACE2 were reduced to thiols, the binding became thermodynamically unfavorable. In both cases, the binding free energies have positive values; Δ_bindG° of CoV^red···ACE2^red and CoV-2^red···ACE2^red are 52.0 and 57.3 kcal/mol, respectively. These results indicate that the binding will be severely impacted, when the disulfides of both interacting proteins are converted to thiols. This finding is potentially significant as it indicates that the cleavage of disulfide bridges in ACE2 has a significant destabilizing effect on the spike protein binding.

2.4. Molecular Basis of the Impaired Binding

The conjoined two helices of ACE2 (residues 19–53 and residues 56–94) form a complementary shape (Figure 5) that fits into the concave-shaped loop-β-sheet-loop motif (residues 460–490 of CoV and residues 475–505 of CoV-2) of RBD of viral spike proteins. The loss of disulfide bridges in ACE2 had a strong impact on the junction of the two conjoined helices (Figure 5, CoV^red···ACE2^red). This region is close to the disulfide bridge C344:::C361, and its cleavage has a significant impact on the shape complementarity at the protein–protein interface. Similarly, the loss of C467:::C474 disulfide in CoV (C480:::C488 in CoV-2) resulted in a significant conformational change in the loop region, which was displaced away from the protein–protein interface by ∼6 Å, indicating a reduced binding interaction as confirmed by the binding free energy calculations. This conformational change as well as the alteration in the backbone flexibility (Figure 4) must have resulted in impaired binding of CoV/CoV-2 with ACE2.

Figure 5. Comparison of the conformational change at the protein–protein interface in CoV^ox···ACE2^ox (left) and CoV^red···ACE2^red (right). CoV and ACE2 subunits in the complex are shown in blue and red colors, respectively, at the center. The structural motif containing the two helices of ACE2 and a β sheet of the CoV (or CoV-2) was monitored before (top) and after (bottom) 20 ns MD simulation. The left and right panels show the difference in conformational changes in the oxidized form (CoV^ox···ACE2^ox) and reduced form (CoV^red···ACE2^red), respectively.

3. Conclusions

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The study found that the reduction of all disulfides into sulfydryl groups completely impairs the binding of SARS-CoV/CoV-2 spike protein to ACE2. This is evident from the positive Gibbs energy of binding (Δ_bindG°) obtained for both CoV^red···ACE2^red and CoV-2^red···ACE2^red complexes. When the disulfides of only ACE2 were reduced to sulfydryl groups, the binding becomes weaker, as Δ_bindG° becomes less negative by 4–6 kcal/mol with respect to the fully oxidized systems. On the other hand, the reduction of disulfides of the RBD of CoV-2 has comparatively less effect on Δ_bindG°, while the reduction of disulfides in CoV RBD does not impact the binding with ACE2. This finding is consistent with the observed redox insensitivity of the binding between CoV and ACE2. (7)

The redox environment of cell surface receptors is regulated by the thiol–disulfide equilibrium in the extracellular region. (12,18) This is maintained by glutathione transporters, (19) a number of oxidoreductases (12) including protein disulfide isomerase, (8) and several redox switches. (12) Under oxidative stress, the extracellular environment becomes oxidation-prone resulting in more disulfide formation on protein surfaces. (12) Therefore, under severe oxidative stress, the cell surface receptor ACE2 and RBD of the intruding viral spike protein are likely to be present in its oxidized form having predominantly disulfide linkages. This computational study shows that under oxidative stress, the lack of a reducing environment would result in significantly favorable binding of the viral protein on the cell surface ACE2. In terms of energetics, this computational study demonstrates that the oxidized form of proteins with disulfide bridges would cause more than 50 kcal/mol of decrease in Gibbs binding free energy. Furthermore, ACE2, which the viral spike proteins latch on to, is known to be a key player in the remedial of oxidative stress. (20) Binding of the viral protein will prevent the key catalytic function of ACE2 of converting angiotensin 2 (a strong activator of oxidative stress) to angiotensin 1–7 thereby creating a vicious circle of enhanced viral attack. In summary, the present study demonstrates that the absence of or reduced oxidative stress would have a significant beneficial effect during the early stage of viral infection by preventing viral protein binding on the host cells.

4. Methodology

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4.1. Computational Setup

Setting up of protein systems and all structural manipulations were carried out using visual molecular dynamics (VMD). (21) Disulfide groups were modified to thiols during the setting up of structures using standard VMD scripts. Molecular optimization and dynamics (MD) simulations were carried out using nanoscale molecular dynamics (NAMD) package using CHARMM36 force field. (22−26) During MD simulations, electrostatic energy calculations were carried out using the particle mesh Ewald method. (27) Backbone root-mean-square-deviation (RMSD) calculations were performed using VMD. Protein–protein interactions were studied using adaptive-basis Poisson–Boltzmann solver (APBS). (28) Electrostatic field calculations were performed using PDB 2PQR program suit. (29)

4.2. Molecular Dynamics Simulations

All simulations were performed using the structure of ACE2 bound SARS-CoV (PDB entry: 3D0G) (13) and SARS-CoV-2 (PDB entry: 6M0J). (15) In all simulations, set up of protein complex systems was carried out following protocols used in the previous studies from this lab. (17,30) Briefly, hydrogens were added using the HBUILD module of CHARMM. Ionic amino acid residues were maintained in a protonation state corresponding to pH 7. The protonation state of histidine residues was determined by computing the pK_a using the Propka option of PDB 2PQR. The protein structures were explicitly solvated with water of the TIP3P model and neutralized by adding with 24 sodium atoms. The prepared solvated protein complexes were of dimensions 92 Å × 132 Å × 104 Å for SARS-CoV and 94 Å × 144 Å × 100 Å for SARS-CoV-2 systems. (21)

All systems were subjected to equilibration for 50 ps. Following equilibration, 20 ns MD simulations were performed for each system. The velocities and positions of atoms during dynamics were calculated using the velocity Verlet integration algorithm (31) using a time step of 2.0 fs. All simulations were run with NAMD implementation of Langevin dynamics (32) at a constant temperature of 298 K using periodic boundary conditions. To model, nonbonding interactions, a switching function was turned on with a “switchdist” of 10 Å, a cutoff of 14 Å, and a “pairlistdist” of 16 Å.

4.3. Binding Free Energy Calculations

Gibbs free energies of binding between the ACE2 and SARS-CoV or CoV-2 proteins were calculated using APBS, a standardized method of a treecode-accelerated boundary integral Poisson–Boltzmann (TABI-PB) equation solver. (33) In this method, the protein surface is triangulated and electrostatic surface potentials are computed. The discretization of surface potentials is utilized to compute the net energy due to solvation as well as electrostatic interactions between the two protein subunits, as outlined in the thermodynamic scheme (Scheme 1). Following Scheme 1, the free energy of binding of the two protein fragments in water can be expressed as a sum of two components (eq 1)

(1)

where Δ_CoulG represents the Coulombic (electrostatic) interactions between the proteins occurring at the protein–protein interface (Scheme 1) and ΔΔ_solvG is the difference of the solvation energies between the complex and the corresponding free proteins

(2)

However, the solvation calculation used only part of the entire spike protein as well as the ACE2; therefore, Δ_bindG_TABI-PB was calibrated by correcting ΔΔ_solvG using experimentally known binding free energy of ACE2···CoV-2

(3)

where K_d = 37 nM is the experimental dissociation constant. (16)

The corrected free energy of the solvation

(4)

Using ΔG_corr and eq 4, the corrected binding free energy, Δ_bindG°, of all protein complexes is expressed by

(5)

As shown in eq 4, the combination of the last two terms in eq 5 is equal to ΔΔ_solvG_corr. Therefore, eq 5 can be simplified as

(6)

Author Information

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Corresponding Author
- Sudeep Bhattacharyya - Department of Chemistry, University of Wisconsin—Eau Claire, Eau Claire, Wisconsin 54701, United States; http://orcid.org/0000-0002-3960-1239; Email: [email protected]
Author
- Sanchita Hati - Department of Chemistry, University of Wisconsin—Eau Claire, Eau Claire, Wisconsin 54701, United States
Funding
This work was supported in part by the National Institute of Health (grant number 1R15GM117510-01 to S.H. and S.B.).
Notes
The authors declare no competing financial interest.

Acknowledgments

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We acknowledge computational support from the Blugold Super Computing Cluster (BGSC) of the University of Wisconsin—Eau Claire.

Abbreviations Used

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ACE	angiotensin-converting enzyme
CoV	coronavirus
MD	molecular dynamics
RBD	receptor-binding domain
TABI-PB	treecode-accelerated boundary integral Poisson–Boltzmann

References

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Xu, H.; Zhong, L.; Deng, J.; Peng, J.; Dan, H.; Zeng, X.; Li, T.; Chen, Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci. 2020, 12, 8 DOI: 10.1038/s41368-020-0074-x
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High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
Xu, Hao; Zhong, Liang; Deng, Jiaxin; Peng, Jiakuan; Dan, Hongxia; Zeng, Xin; Li, Taiwen; Chen, Qianming
International Journal of Oral Science (2020), 12 (1), 8CODEN: IJOSFA; ISSN:2049-3169. (Nature Research)
It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Anal. of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated inhouse were used to identify and confirm the ACE2-expressing cell compn. and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clin. practice as well as daily life.
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Ryser, H. J.; Levy, E. M.; Mandel, R.; DiSciullo, G. J. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4559– 4563, DOI: 10.1073/pnas.91.10.4559
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Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction
Ryser, Hugues J.-P.; Levy, Elinor M.; Mandel, Richard; DiSciullo, Gino J.
Proceedings of the National Academy of Sciences of the United States of America (1994), 91 (10), 4559-63CODEN: PNASA6; ISSN:0027-8424.
The cell surface of mammalian cells is capable of reductively cleaving disulfide bonds of exogenous membrane-bound macromols. (for instance, the interchain disulfide of diphtheria toxin), and inhibiting this process with membrane-impermeant sulfhydryl reagents prevents diphtheria toxin cytotoxicity. More recently it was found that the same membrane function can be inhibited by bacitracin, an inhibitor of protein disulfide-isomerase (PDI), and by monoclonal antibodies against PDI, suggesting that PDI catalyzes a thiol-disulfide interchange between its thiols and the disulfides of membrane-bound macromols. The authors provide evidence that the same reductive process plays a role in the penetration of membrane-bound human immunodeficiency virus (HIV) and show that HIV infection of human lymphoid cells is markedly inhibited by the membrane-impermeant sulfhydryl blocker 5,5'-dithiobis(2-nitrobenzoic acid), by bacitracin, and by anti-PDI antibodies. The results imply that HIV and its target cell engage in a thiol-disulfide interchange mediated by PDI and that the redn. of crit. disulfides in viral envelope glycoproteins may be the initial event that triggers conformational changes required for HIV entry and cell infection. These findings suggest addnl. approaches to impede cell infection by HIV.
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Gallina, A.; Hanley, T. M.; Mandel, R.; Trahey, M.; Broder, C. C.; Viglianti, G. A.; Ryser, H. J. Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J. Biol. Chem. 2002, 277, 50579– 50588, DOI: 10.1074/jbc.M204547200
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Inhibitors of Protein-Disulfide Isomerase Prevent Cleavage of Disulfide Bonds in Receptor-bound Glycoprotein 120 and Prevent HIV-1 Entry
Gallina, Angelo; Hanley, Timothy M.; Mandel, Richard; Trahey, Meg; Broder, Christopher C.; Viglianti, Gregory A.; Ryser, Hugues J.-P.
Journal of Biological Chemistry (2002), 277 (52), 50579-50588CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
We previously reported that monoclonal antibodies to protein-disulfide isomerase (PDI) and other membrane-impermeant PDI inhibitors prevented HIV-1 infection. PDI is present at the surface of HIV-1 target cells and reduces disulfide bonds in a model peptide attached to the cell membrane. Here we show that sol. PDI cleaves disulfide bonds in recombinant envelope glycoprotein gp120 and that gp120 bound to the surface receptor CD4 undergoes a disulfide redn. that is prevented by PDI inhibitors. Concns. of inhibitors that prevent this redn. and inhibit the cleavage of surface-bound disulfide conjugate prevent infection at the level of HIV-1 entry. The entry of HIV-1 strains differing in their coreceptor specificities is similarly inhibited, and so is the redn. of gp120 bound to CD4 of coreceptor-neg. cells. PDI inhibitors also prevent HIV envelope-mediated cell-cell fusion but have no effect on the entry of HIV-1 pseudo-typed with murine leukemia virus envelope. Importantly, PDI coppts. with both sol. and cellular CD4. We propose that a PDI·CD4 assocn. at the cell surface enables PDI to reach CD4-bound virus and to reduce disulfide bonds present in the domain of gp120 that binds to CD4. Conformational changes resulting from the opening of gp120-disulfide loops may drive the processes of virus-cell and cell-cell fusion. The biochem. events described identify new potential targets for anti-HIV agents.
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Lavillette, D.; Barbouche, R.; Yao, Y.; Boson, B.; Cosset, F. L.; Jones, I. M.; Fenouillet, E. Significant redox insensitivity of the functions of the SARS-CoV spike glycoprotein: comparison with HIV envelope. J. Biol. Chem. 2006, 281, 9200– 9204, DOI: 10.1074/jbc.M512529200
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Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein: Comparison with HIV envelope
Lavillette, Dimitri; Barbouche, Rym; Yao, Yongxiu; Boson, Bertrand; Cosset, Francois-Loic; Jones, Ian M.; Fenouillet, Emmanuel
Journal of Biological Chemistry (2006), 281 (14), 9200-9204CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
The capacity of the surface glycoproteins of enveloped viruses to mediate virus/cell binding and membrane fusion requires a proper thiol/disulfide balance. Chem. manipulation of their redox state using reducing agents or free sulfhydryl reagents affects virus/cell interaction. Conversely, natural thiol/disulfide rearrangements often occur during the cell interaction to trigger fusogenicity, hence the virus entry. We examd. the relationship between the redox state of the 20 cysteine residues of the SARS-CoV (severe acute respiratory syndrome coronavirus) Spike glycoprotein S1 subdomain and its functional properties. Mature S1 exhibited ∼4 unpaired cysteines, and chem. reduced S1 displaying up to ∼6 addnl. unpaired cysteines still bound ACE2 and enabled fusion. In addn., virus/cell membrane fusion occurred in the presence of sulfhydryl-blocking reagents and oxidoreductase inhibitors. Thus, in contrast to various viruses including HIV (human immunodeficiency virus) examd. in parallel, the functions of the SARS-CoV Spike glycoprotein exhibit a significant and surprising independence of redox state, which may contribute to the wide host range of the virus. These data suggest clues for molecularly engineering vaccine immunogens.
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Pan, S.; Chen, H. H.; Correia, C.; Dai, H.; Witt, T. A.; Kleppe, L. S.; Burnett, J. C., Jr.; Simari, R. D. Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate. PLoS One 2014, 9, e112986 DOI: 10.1371/journal.pone.0112986
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Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate
Pan, Shuchong; Chen, Horng H.; Correia, Cristina; Dai, Haiming; Witt, Tyra A.; Kleppe, Laurel S.; Burnett, John C., Jr.; Simari, Robert D.
PLoS One (2014), 9 (11), e112986/1-e112986/14, 14 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Rationale: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. Objective: We utilized complementary in vitro and in vivo models to det. the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. Methods and Results: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addn. of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochem. Conclusion: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors.
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Mathys, L.; Balzarini, J. The role of cellular oxidoreductases in viral entry and virus infection-associated oxidative stress: potential therapeutic applications. Expert Opin. Ther. Targets 2016, 20, 123– 143, DOI: 10.1517/14728222.2015.1068760
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The role of cellular oxidoreductases in viral entry and virus infection-associated oxidative stress: potential therapeutic applications
Mathys, Leen; Balzarini, Jan
Expert Opinion on Therapeutic Targets (2016), 20 (1), 123-143CODEN: EOTTAO; ISSN:1472-8222. (Taylor & Francis Ltd.)
Cellular oxidoreductases catalyze thiol/disulfide exchange reactions in susceptible proteins and contribute to the cellular defense against oxidative stress. Oxidoreductases and oxidative stress are also involved in viral infections. In this overview, different aspects of the role of cellular oxidoreductases and oxidative stress during viral infections are discussed from a chemotherapeutic viewpoint. Entry of enveloped viruses into their target cells is triggered by the interaction of viral envelope glycoproteins with cellular (co)receptor(s) and depends on obligatory conformational changes in these viral envelope glycoproteins and/or cellular receptors. For some viruses, these conformational changes are mediated by cell surface-assocd. cellular oxidoreductases, which mediate disulfide bridge redns. in viral envelope glycoprotein(s). Therefore, targeting these oxidoreductases using oxidoreductase inhibitors might yield an interesting strategy to block viral entry of these viruses. Furthermore, since viral infections are often assocd. with systemic oxidative stress, contributing to disease progression, the enhancement of the cellular antioxidant defense systems might have potential as an adjuvant antiviral strategy, slowing down disease progression. Promising antiviral data were obtained for both strategies. However, potential pitfalls have also been identified for these strategies, indicating that it is important to carefully assess the benefits vs. risks of these antiviral strategies.
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Camini, F. C.; da Silva Caetano, C. C.; Almeida, L. T.; de Brito Magalhães, C. L. Implications of oxidative stress on viral pathogenesis. Arch. Virol. 2017, 162, 907– 917, DOI: 10.1007/s00705-016-3187-y
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Implications of oxidative stress on viral pathogenesis
Camini, Fernanda Caetano; Caetano, Camila Carla da Silva; Almeida, Leticia Trindade; Magalhaes, Cintia Lopes de Brito
Archives of Virology (2017), 162 (4), 907-917CODEN: ARVIDF; ISSN:0304-8608. (Springer-Verlag GmbH)
Reactive species are frequently formed after viral infections. Antioxidant defences, including enzymic and non-enzymic components, protect against reactive species, but sometimes these defences are not completely adequate. An imbalance in the prodn. of reactive species and the body's inability to detoxify these reactive species is referred to as oxidative stress. The aim of this review is to analyze the role of oxidative stress in the pathogenesis of viral infections and highlight some major therapeutic approaches that have gained importance, with regards to controlling virus-induced oxidative injury. Attention will be focused on DNA viruses (papillomaviruses, hepadnaviruses), RNA viruses (flaviviruses, orthomyxoviruses, paramyxoviruses, togaviruses) and retroviruses (human immunodeficiency virus). In general, viruses cause an imbalance in the cellular redox environment, which depending on the virus and the cell can result in different responses, e.g. cell signaling, antioxidant defences, reactive species, and other processes. Therefore, the modulation of reactive species prodn. and oxidative stress potentially represents a novel pharmacol. approach for reducing the consequences of viral pathogenesis.
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Fenouillet, E.; Barbouche, R.; Jones, I. M. Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus. Antioxid. Redox Signaling 2007, 9, 1009– 1034, DOI: 10.1089/ars.2007.1639
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Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus
Fenouillet, Emmanuel; Barbouche, Rym; Jones, Ian M.
Antioxidants & Redox Signaling (2007), 9 (8), 1009-1034CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)
A review. For enveloped viruses, genome entry into the target cell involves two major steps: virion binding to the cell-surface receptor and fusion of the virion and cell membranes. Virus-cell membrane fusion is mediated by the virus envelope complex, and its fusogenicity is the result of an active virus-cell interaction process that induces conformation changes within the envelope. For some viruses, such as influenza, exposure to an acidic milieu within the cell during the early steps of infection triggers the necessary structural changes. However, for other pathogens which are not exposed to such environmental stress, activation of fusogenicity can result from precise thiol/disulfide rearrangements mediated by either an endogenous redox autocatalytic isomerase or a cell-assocd. oxidoreductase. Study of the activation of HIV envelope fusogenicity has revealed new knowledge about how redox changes within a viral envelope trigger fusion. We discuss these findings and their implication for anti-HIV therapy. In addn., to compare and contrast the situation outlined for HIV with an enveloped virus that can fuse with the cell plasma membrane independent of the redox status of its envelope protein, we review parallel data obtained on SARS coronavirus entry.
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Yi, M. C.; Khosla, C. Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment. Annu. Rev. Chem. Biomol. Eng. 2016, 7, 197– 222, DOI: 10.1146/annurev-chembioeng-080615-033553
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Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment
Yi, Michael C.; Khosla, Chaitan
Annual Review of Chemical and Biomolecular Engineering (2016), 7 (), 197-222CODEN: ARCBCY; ISSN:1947-5438. (Annual Reviews)
Disulfide bonds represent versatile posttranslational modifications whose roles encompass the structure, catalysis, and regulation of protein function. Due to the oxidizing nature of the extracellular environment, disulfide bonds found in secreted proteins were once believed to be inert. This notion has been challenged by the discovery of redox-sensitive disulfides that, once cleaved, can lead to changes in protein activity. These functional disulfides are twisted into unique configurations, leading to high strain and potential energy. In some cases, cleavage of these disulfides can lead to a gain of function in protein activity. Thus, these motifs can be referred to as switches. We describe the couples that control redox in the extracellular environment, examine several examples of proteins with switchable disulfides, and discuss the potential applications of disulfides in mol. biol.
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Li, F. Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. J. Virol. 2008, 82, 6984– 6991, DOI: 10.1128/JVI.00442-08
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Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections
Li, Fang
Journal of Virology (2008), 82 (14), 6984-6991CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
It is believed that a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), was passed from palm civets to humans and caused the epidemic of SARS in 2002 to 2003. The major species barriers between humans and civets for SARS-CoV infections are the specific interactions between a defined receptor-binding domain (RBD) on a viral spike protein and its host receptor, angiotensin-converting enzyme 2 (ACE2). In this study a chimeric ACE2 bearing the crit. N-terminal helix from civet and the remaining peptidase domain from human was constructed, and it was shown that this construct has the same receptor activity as civet ACE2. In addn., crystal structures of the chimeric ACE2 complexed with RBDs from various human and civet SARS-CoV strains were detd. These structures, combined with a previously detd. structure of human ACE2 complexed with the RBD from a human SARS-CoV strain, have revealed a structural basis for understanding the major species barriers between humans and civets for SARS-CoV infections. They show that the major species barriers are detd. by interactions between four ACE2 residues (residues 31, 35, 38, and 353) and two RBD residues (residues 479 and 487), that early civet SARS-CoV isolates were prevented from infecting human cells due to imbalanced salt bridges at the hydrophobic virus/receptor interface, and that SARS-CoV has evolved to gain sustained infectivity for human cells by eliminating unfavorable free charges at the interface through stepwise mutations at positions 479 and 487. These results enhance our understanding of host adaptations and cross-species infections of SARS-CoV and other emerging animal viruses.
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Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C. L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020, 367, 1260– 1263, DOI: 10.1126/science.abb2507
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Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.
Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
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Wang, Q.; Zhang, Y.; Wu, L.; Niu, S.; Song, C.; Zhang, Z.; Lu, G.; Qiao, C.; Hu, Y.; Yuen, K. Y.; Wang, Q.; Zhou, H.; Yan, J.; Qi, J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 2020, 181, 894– 904.e9, DOI: 10.1016/j.cell.2020.03.045
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Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2
Wang, Qihui; Zhang, Yanfang; Wu, Lili; Niu, Sheng; Song, Chunli; Zhang, Zengyuan; Lu, Guangwen; Qiao, Chengpeng; Hu, Yu; Yuen, Kwok-Yung; Wang, Qisheng; Zhou, Huan; Yan, Jinghua; Qi, Jianxun
Cell (Cambridge, MA, United States) (2020), 181 (4), 894-904.e9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that obsd. for SARS-CoV. However, at. details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Addnl., a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
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Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020, 367, 1444– 1448, DOI: 10.1126/science.abb2762
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Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang
Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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Adams, L. M.; Andrews, R. J.; Hu, Q. H.; Schmit, H. L.; Hati, S.; Bhattacharyya, S. Crowder-Induced Conformational Ensemble Shift in Escherichia coli Prolyl-tRNA Synthetase. Biophys. J. 2019, 117, 1269– 1284, DOI: 10.1016/j.bpj.2019.08.033
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Crowder-Induced Conformational Ensemble Shift in Escherichia coli Prolyl-tRNA Synthetase
Adams, Lauren M.; Andrews, Ryan J.; Hu, Quin H.; Schmit, Heidi L.; Hati, Sanchita; Bhattacharyya, Sudeep
Biophysical Journal (2019), 117 (7), 1269-1284CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
The effect of mol. crowding on the structure and function of Escherichia coli prolyl-tRNA synthetase (Ec ProRS), a member of the aminoacyl-tRNA synthetase family, has been investigated using a combined exptl. and theor. method. Ec ProRS is a multidomain enzyme; coupled-domain dynamics are essential for efficient catalysis. To gain insight into the mechanistic detail of the crowding effect, kinetic studies were conducted with varying concns. and sizes of crowders. In parallel, spectroscopic and quantum chem. studies were employed to probe the "soft interactions" between crowders and protein side chains. Finally, the dynamics of the dimeric protein was examd. in the presence of crowders using a long-duration (70 ns) classical mol. dynamic simulations. The results of the simulations revealed a shift in the conformational ensemble, which is consistent with the preferential exclusion of cosolutes. The "soft interactions" model of the crowding effect also explained the alteration in kinetic parameters. In summary, the study found that the effects of mol. crowding on both conformational dynamics and catalytic function are correlated in the multidomain Ec ProRS, an enzyme that is central to protein synthesis in all living cells. This study affirmed that large and small cosolutes have considerable impacts on the structure, dynamics, and function of modular proteins and therefore must be considered for stabilizing protein-based pharmaceuticals and industrial enzymes.
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Bechtel, T. J.; Weerapana, E. From structure to redox: The diverse functional roles of disulfides and implications in disease. Proteomics 2017, 17, 1600391 DOI: 10.1002/pmic.201600391
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Ballatori, N.; Krance, S. M.; Marchan, R.; Hammond, C. L. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol. Aspects Med. 2009, 30, 13– 28, DOI: 10.1016/j.mam.2008.08.004
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Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology
Ballatori, Nazzareno; Krance, Suzanne M.; Marchan, Rosemarie; Hammond, Christine L.
Molecular Aspects of Medicine (2009), 30 (1-2), 13-28CODEN: MAMED5; ISSN:0098-2997. (Elsevier B.V.)
A review. Reduced glutathione (GSH) is crit. for many cellular processes, and both its intracellular and extracellular concns. are tightly regulated. Intracellular GSH levels are regulated by two main mechanisms: by adjusting the rates of synthesis and of export from cells. Some of the proteins responsible for GSH export from mammalian cells have recently been identified, and there is increasing evidence that these GSH exporters are multispecific and multifunctional, regulating a no. of key biol. processes. In particular, some of the multidrug resistance-assocd. proteins (Mrp/Abcc) appear to mediate GSH export and homeostasis. The Mrp proteins mediate not only GSH efflux, but they also export oxidized glutathione derivs. (e.g., glutathione disulfide (GSSG), S-nitrosoglutathione (GS-NO), and glutathione-metal complexes), as well as other glutathione S-conjugates. The ability to export both GSH and oxidized derivs. of GSH, endows these transporters with the capacity to directly regulate the cellular thiol-redox status, and therefore the ability to influence many key signaling and biochem. pathways. Among the many processes that are influenced by the GSH transporters are apoptosis, cell proliferation, and cell differentiation. This report summarizes the evidence that Mrps contribute to the regulation of cellular GSH levels and the thiol-redox state, and thus to the many biochem. processes that are influenced by this tripeptide.
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Xia, H.; Suda, S.; Bindom, S.; Feng, Y.; Gurley, S. B.; Seth, D.; Navar, L. G.; Lazartigues, E. ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS One 2011, 6, e22682 DOI: 10.1371/journal.pone.0022682
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ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function
Xia, Huijing; Suda, Sonia; Bindom, Sharell; Feng, Yumei; Gurley, Susan B.; Seth, Dale; Navar, L. Gabriel; Lazartigues, Eric
PLoS One (2011), 6 (7), e22682CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a redn. of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2-/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 wk). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2-/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2-/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2-/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also obsd. on baseline in mature ACE2-/y mice (48 wk). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2-/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-assocd. dysautonomia and oxidative stress.
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Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graphics 1996, 14, 33– 38, DOI: 10.1016/0263-7855(96)00018-5
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VDM: visual molecular dynamics
Humphrey, William; Dalke, Andrew; Schulten, Klaus
Journal of Molecular Graphics (1996), 14 (1), 33-8, plates, 27-28CODEN: JMGRDV; ISSN:0263-7855. (Elsevier)
VMD is a mol. graphics program designed for the display and anal. of mol. assemblies, in particular, biopolymers such as proteins and nucleic acids. VMD can simultaneously display any no. of structures using a wide variety of rendering styles and coloring methods. Mols. are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resoln. raster images of displayed mols. may be produced by generating input scripts for use by a no. of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate mol. dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biol., which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs, VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
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Guvench, O.; Hatcher, E.; Venable, R. M.; Pastor, R. W.; MacKerell, A. D. CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses. J. Chem. Theory Comput. 2009, 5, 2353– 2370, DOI: 10.1021/ct900242e
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CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses
Guvench, Olgun; Hatcher, Elizabeth; Venable, Richard M.; Pastor, Richard W.; MacKerell, Alexander D., Jr.
Journal of Chemical Theory and Computation (2009), 5 (9), 2353-2370CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
We present an extension of the CHARMM hexopyranose monosaccharide additive all-atom force field to enable modeling of glycosidic-linked hexopyranose polysaccharides. The new force field parameters encompass 1-1, 1-2, 1-3, 1-4, and 1-6 hexopyranose glycosidic linkages, as well as O-methylation at the C1 anomeric carbon, and are developed to be consistent with the CHARMM all-atom biomol. force fields for proteins, nucleic acids, and lipids. The parameters are developed in a hierarchical fashion using model compds. contg. the key atoms in the full carbohydrates, in particular O-methyl-tetrahydropyran and glycosidic-linked dimers consisting of two mols. of tetrahyropyran or one mol. of tetrahydropyran and one of cyclohexane. Target data for parameter optimization include full two-dimensional energy surfaces defined by the Φ/Ψ glycosidic dihedral angles in the disaccharide analogs, as detd. by quantum mech. MP2/cc-pVTZ single point energies on MP2/6-31G(d) optimized structures (MP2/cc-pVTZ//MP2/6-31G(d)). In order to achieve balanced, transferable dihedral parameters for the Φ/Ψ glycosidic dihedral angles, surfaces for all possible chiralities at the ring carbon atoms involved in the glycosidic linkages are considered, resulting in over 5000 MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. Also included as target data are vibrational frequencies, pair interaction energies and distances with water mols., and intramol. geometries including distortion of the glycosidic valence angle as a function of the glycosidic dihedral angles. The model compd. optimized force field parameters are validated on full disaccharides through the comparison of mol. dynamics results to available exptl. data. Good agreement is achieved with expt. for a variety of properties including crystal cell parameters and intramol. geometries, aq. densities, and aq. NMR coupling consts. assocd. with the glycosidic linkage. The newly developed parameters allow for the modeling of linear, branched, and cyclic hexopyranose glycosides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing CHARMM biomol. force fields.
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Raman, E. P.; Guvench, O.; MacKerell, A. D., Jr. CHARMM additive all-atom force field for glycosidic linkages in carbohydrates involving furanoses. J. Phys. Chem. B 2010, 114, 12981– 12994, DOI: 10.1021/jp105758h
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CHARMM Additive All-Atom Force Field for Glycosidic Linkages in Carbohydrates Involving Furanoses
Raman, E. Prabhu; Guvench, Olgun; MacKerell, Alexander D., Jr.
Journal of Physical Chemistry B (2010), 114 (40), 12981-12994CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
Presented is an extension of the CHARMM additive carbohydrate all-atom force field to enable modeling of polysaccharides contg. furanose sugars. The new force field parameters encompass 1 ↔ 2, 1 → 3, 1 → 4, and 1 → 6 pyranose-furanose linkages and 2 → 1 and 2 → 6 furanose-furanose linkages, building on existing hexopyranose and furanose monosaccharide parameters. The model compds. were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and THF as to contain the key atoms in full carbohydrates. Target data for optimization included two-dimensional quantum mech. (QM) potential energy scans of the Φ/Ψ glycosidic dihedral angles, with geometry optimization at the MP2/6-31G(d) level followed by MP2/cc-pVTZ single-point energies. All possible chiralities of the model compds. at the linkage carbons were considered, and for each geometry, the THF ring was constrained to the favorable south or north conformations. Target data also included QM vibrational frequencies and pair interaction energies and distances with water mols. Force field validation included comparison of computed crystal properties, aq. soln. densities, and NMR J-coupling consts. to exptl. ref. values. Simulations of infinite crystals showed good agreement with exptl. values for intramol. geometries as well as for crystal unit cell parameters. Addnl., aq. soln. densities and available NMR data were reproduced to a high degree of accuracy, thus validating the hierarchically optimized parameters in both cryst. and aq. condensed phases. The newly developed parameters allow for the modeling of linear, branched, and cyclic pyranose/furanose polysaccharides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing additive CHARMM biomol. force fields.
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Guvench, O.; Mallajosyula, S. S.; Raman, E. P.; Hatcher, E.; Vanommeslaeghe, K.; Foster, T. J.; Jamison, F. W., II; Mackerell, A. D., Jr. CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling. J. Chem. Theory Comput. 2011, 7, 3162– 3180, DOI: 10.1021/ct200328p
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CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate-Protein Modeling
Guvench, Olgun; Mallajosyula, Sairam S.; Raman, E. Prabhu; Hatcher, Elizabeth; Vanommeslaeghe, Kenno; Foster, Theresa J.; Jamison, Francis W.; MacKerell, Alexander D.
Journal of Chemical Theory and Computation (2011), 7 (10), 3162-3180CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
Monosaccharide derivs. such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details the development of force-field parameters for these monosaccharides and their covalent connections to proteins via O linkages to serine or threonine side chains and via N linkages to asparagine side chains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small mols. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the mol. simulation of a wide variety of biol. important mols. such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mech. (QM) geometries and conformational energies of model compds., as well as to QM pair interaction energies and distances of model compds. with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallog. data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomol. force field, they further broaden the types of heterogeneous systems accessible with a consistently developed force-field model.
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Best, R. B.; Zhu, X.; Shim, J.; Lopes, P. E. M.; Mittal, J.; Feig, M.; MacKerell, A. D. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. J. Chem. Theory Comput. 2012, 8, 3257– 3273, DOI: 10.1021/ct300400x
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Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone .vphi., ψ and Side-Chain χ1 and χ2 Dihedral Angles
Best, Robert B.; Zhu, Xiao; Shim, Jihyun; Lopes, Pedro E. M.; Mittal, Jeetain; Feig, Michael; MacKerell, Alexander D.
Journal of Chemical Theory and Computation (2012), 8 (9), 3257-3273CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large no. of applications, limitations in the model with respect to the equil. between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non-Gly, -Pro) backbone CMAP potential has been refined against exptl. soln. NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mech. energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mech. energy surfaces, followed by addnl. empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against a collection of exptl. data: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equil. folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for modeling and simulation studies of proteins, including studies of protein folding, assembly, and functionally relevant conformational changes.
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Mallajosyula, S. S.; Guvench, O.; Hatcher, E.; Mackerell, A. D., Jr. CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates. J. Chem. Theory Comput. 2012, 8, 759– 776, DOI: 10.1021/ct200792v
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CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates
Mallajosyula, Sairam S.; Guvench, Olgun; Hatcher, Elizabeth; MacKerell, Alexander D.
Journal of Chemical Theory and Computation (2012), 8 (2), 759-776CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
Presented is an extension of the CHARMM additive all-atom carbohydrate force field to enable the modeling of phosphate and sulfate linked to carbohydrates. The parameters are developed in a hierarchical fashion using model compds. contg. the key atoms in the full carbohydrates. Target data for parameter optimization included full two-dimensional energy surfaces defined by the glycosidic dihedral angle pairs in the phosphate/sulfate model compd. analogs of hexopyranose monosaccharide phosphates and sulfates, as detd. by quantum mech. (QM) MP2/cc-pVTZ single point energies on MP2/6-31+G(d) optimized structures. To achieve balanced, transferable dihedral parameters for the dihedral angles, surfaces for all possible anomeric and conformational states were included during the parametrization process. To model physiol. relevant systems, both the mono- and dianionic charged states were studied for the phosphates. This resulted in over 7000 MP2/cc-pVTZ//MP2/6-31G+(d) model compd. conformational energies which, supplemented with QM geometries, were the main target data for the parametrization. Parameters were validated against crystals of relevant monosaccharide derivs. obtained from the Cambridge Structural Database (CSD) and larger systems, inositol-(tri/tetra/penta) phosphates noncovalently bound to the pleckstrin homol. (PH) domain and oligomeric chondroitin sulfate in soln. and in complex with cathepsin K protein.
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Essmann, U.; Perera, L.; Berkowitz, M. L. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577, DOI: 10.1063/1.470117
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A smooth particle mesh Ewald method
Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.; Darden, Tom; Lee, Hsing; Pedersen, Lee G.
Journal of Chemical Physics (1995), 103 (19), 8577-93CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
The previously developed particle mesh Ewald method is reformulated in terms of efficient B-spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p ≥ 1. Furthermore, efficient calcn. of the virial tensor follows. Use of B-splines in the place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. The authors demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomol. systems with many thousands of atoms and this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 Å or less.
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Jurrus, E.; Engel, D.; Star, K.; Monson, K.; Brandi, J.; Felberg, L. E.; Brookes, D. H.; Wilson, L.; Chen, J.; Liles, K.; Chun, M.; Li, P.; Gohara, D. W.; Dolinsky, T.; Konecny, R.; Koes, D. R.; Nielsen, J. E.; Head-Gordon, T.; Geng, W.; Krasny, R.; Wei, G. W.; Holst, M. J.; McCammon, J. A.; Baker, N. A. Improvements to the APBS biomolecular solvation software suite. Protein Sci. 2018, 27, 112– 128, DOI: 10.1002/pro.3280
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Improvements to the APBS biomolecular solvation software suite
Jurrus, Elizabeth; Engel, Dave; Star, Keith; Monson, Kyle; Brandi, Juan; Felberg, Lisa E.; Brookes, David H.; Wilson, Leighton; Chen, Jiahui; Liles, Karina; Chun, Minju; Li, Peter; Gohara, David W.; Dolinsky, Todd; Konecny, Robert; Koes, David R.; Nielsen, Jens Erik; Head-Gordon, Teresa; Geng, Weihua; Krasny, Robert; Wei, Guo-Wei; Holst, Michael J.; McCammon, J. Andrew; Baker, Nathan A.
Protein Science (2018), 27 (1), 112-128CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomol. assemblages that have provided impact in the study of a broad range of chem., biol., and biomedical applications. APBS addresses the three key technol. challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomol. solvation and electrostatics, robust and scalable software for applying those theories to biomol. systems, and mechanisms for sharing and analyzing biomol. electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson-Boltzmann anal. and a semi-anal. solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory-based algorithm for detg. pKa values, and an improved web-based visualization tool for viewing electrostatics.
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Dolinsky, T. J.; Czodrowski, P.; Li, H.; Nielsen, J. E.; Jensen, J. H.; Klebe, G.; Baker, N. A. PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations. Nucleic Acids Res. 2007, 35, W522– W525, DOI: 10.1093/nar/gkm276
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PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations
Dolinsky Todd J; Czodrowski Paul; Li Hui; Nielsen Jens E; Jensen Jan H; Klebe Gerhard; Baker Nathan A
Nucleic acids research (2007), 35 (Web Server issue), W522-5 ISSN:.
Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pK(a) values, binding constants of ligands, and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systems- and genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665-W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pK(a) estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http://pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization.
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Johnson, J. M.; Sanford, B. L.; Strom, A. M.; Tadayon, S. N.; Lehman, B. P.; Zirbes, A. M.; Bhattacharyya, S.; Musier-Forsyth, K.; Hati, S. Multiple pathways promote dynamical coupling between catalytic domains in Escherichia coli prolyl-tRNA synthetase. Biochemistry 2013, 52, 4399– 4412, DOI: 10.1021/bi400079h
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Multiple Pathways Promote Dynamical Coupling between Catalytic Domains in Escherichia coli Prolyl-tRNA Synthetase
Johnson, James M.; Sanford, Brianne L.; Strom, Alexander M.; Tadayon, Stephanie N.; Lehman, Brent P.; Zirbes, Arrianna M.; Bhattacharyya, Sudeep; Musier-Forsyth, Karin; Hati, Sanchita
Biochemistry (2013), 52 (25), 4399-4412CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Aminoacyl-tRNA synthetases are multidomain enzymes that catalyze covalent attachment of amino acids to their cognate tRNA. Cross-talk between functional domains is a prerequisite for this process. In this study, we investigate the mol. mechanism of site-to-site communication in Escherichia coli prolyl-tRNA synthetase (Ec ProRS). Earlier studies have demonstrated that evolutionarily conserved and/or co-evolved residues that are engaged in correlated motion are crit. for the propagation of functional conformational changes from one site to another in modular proteins. Here, mol. simulation and bioinformatics-based anal. were performed to identify dynamically coupled and evolutionarily constrained residues that form contiguous pathways of residue-residue interactions between the aminoacylation and editing domains of Ec ProRS. The results of this study suggest that multiple pathways exist between these two domains to maintain the dynamic coupling essential for enzyme function. Moreover, residues in these interaction networks are generally highly conserved. Site-directed changes of on-pathway residues have a significant impact on enzyme function and dynamics, suggesting that any perturbation along these pathways disrupts the native residue-residue interactions that are required for effective communication between the two functional domains. Free energy anal. revealed that communication between residues within a pathway and cross-talk between pathways are important for coordinating functions of different domains of Ec ProRS for efficient catalysis.
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Verlet, L. Computer “experiments” on classic fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys. Rev. 1967, 159, 98– 103, DOI: 10.1103/PhysRev.159.98
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Computer "experiments" on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules
Verlet, Loup
Physical Review (1967), 159 (1), 98-103CODEN: PHRVAO; ISSN:0031-899X.
The equation of motion of a system of 864 particles interacting through a Lennard-Jones potential was integrated for various values of the temp. and d., relative, generally, to a fluid state. The equil. properties agree with the corresponding properties of Ar. The equil. state of Ar can be described through a 2-body potential.
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Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kalé, L.; Schulten, K. Scalable molecular dynamics with NAMD. J. Comput. Chem. 2005, 26, 1781– 1802, DOI: 10.1002/jcc.20289
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Scalable molecular dynamics with NAMD
Phillips, James C.; Braun, Rosemary; Wang, Wei; Gumbart, James; Tajkhorshid, Emad; Villa, Elizabeth; Chipot, Christophe; Skeel, Robert D.; Kale, Laxmikant; Schulten, Klaus
Journal of Computational Chemistry (2005), 26 (16), 1781-1802CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
NAMD is a parallel mol. dynamics code designed for high-performance simulation of large biomol. systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical mol. dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temp. and pressure controls used. Features for steering the simulation across barriers and for calcg. both alchem. and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomol. system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the mol. graphics/sequence anal. software VMD and the grid computing/collab. software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
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Geng, W.; Krasny, R. A treecode-accelerated boundary integral Poisson–Boltzmann solver for electrostatics of solvated biomolecules. J. Comput. Phys. 2013, 247, 62– 78, DOI: 10.1016/j.jcp.2013.03.056
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A treecode-accelerated boundary integral Poisson-Boltzmann solver for electrostatics of solvated biomolecules
Geng, Weihua; Krasny, Robert
Journal of Computational Physics (2013), 247 (), 62-78CODEN: JCTPAH; ISSN:0021-9991. (Elsevier Inc.)
We present a treecode-accelerated boundary integral (TABI) solver for electrostatics of solvated biomols. described by the linear Poisson-Boltzmann equation. The method employs a well-conditioned boundary integral formulation for the electrostatic potential and its normal deriv. on the mol. surface. The surface is triangulated and the integral equations are discretized by centroid collocation. The linear system is solved by GMRES iteration and the matrix-vector product is carried out by a Cartesian treecode which reduces the cost from O(N2) to O(NlogN), where N is the no. of faces in the triangulation. The TABI solver is applied to compute the electrostatic solvation energy in two cases, the Kirkwood sphere and a solvated protein. We present the error, CPU time, and memory usage, and compare results for the Poisson-Boltzmann and Poisson equations. We show that the treecode approxn. error can be made smaller than the discretization error, and we compare two versions of the treecode, one with uniform clusters and one with non-uniform clusters adapted to the mol. surface. For the protein test case, we compare TABI results with those obtained using the grid-based APBS code, and we also present parallel TABI simulations using up to eight processors. We find that the TABI solver exhibits good serial and parallel performance combined with relatively simple implementation, efficient memory usage, and geometric adaptability.
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Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215– 220, DOI: 10.1038/s41586-020-2180-5
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Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong; Zhang, Qi; Shi, Xuanling; Wang, Qisheng; Zhang, Linqi; Wang, Xinquan
Nature (London, United Kingdom) (2020), 581 (7807), 215-220CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
Abstr.: A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from Dec. 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an at. level, we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural anal. identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analyzed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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Madeira, F.; Park, Y. M.; Lee, J.; Buso, N.; Gur, T.; Madhusoodanan, N.; Basutkar, P.; Tivey, A. R. N.; Potter, S. C.; Finn, R. D.; Lopez, R. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 2019, 47, W636– W641, DOI: 10.1093/nar/gkz268
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The EMBL-EBI search and sequence analysis tools APIs in 2019
Madeira, Fabio; Park, Young Mi; Lee, Joon; Buso, Nicola; Gur, Tamer; Madhusoodanan, Nandana; Basutkar, Prasad; Tivey, Adrian R. N.; Potter, Simon C.; Finn, Robert D.; Lopez, Rodrigo
Nucleic Acids Research (2019), 47 (W1), W636-W641CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
The EMBL-EBI provides free access to popular bioinformatics sequence anal. applications as well as to a full-featured text search engine with powerful cross-referencing and data retrieval capabilities. Access to these services is provided via user-friendly web interfaces and via established RESTful and SOAP Web Services APIs (https://www.ebi.ac.uk/seqdb/confluence/display/JDSAT/EMBL-EBI+Web+Services+APIs+-+Data+Retrieval). Both systems have been developed with the same core principles that allow them to integrate an ever-increasing vol. of biol. data, making them an integral part of many popular data resources provided at the EMBL-EBI. Here, we describe the latest improvements made to the frameworks which enhance the interconnectivity between public EMBL-EBI resources and ultimately enhance biol. data discoverability, accessibility, interoperability and reusability.
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Figure 1
Figure 1. Sequence alignment (generated by Clustal Omega (35)) between the receptor-binding domain of SARS-CoV and SARS-CoV-2 proteins. “*” represents the identical residues, “:” and “.” represent strongly and weakly similar residues, respectively, and gap represents dissimilar residues. The cysteine residues are highlighted in yellow.
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Figure 2
Figure 2. Structures of protein complexes: (a) SARS-CoV···ACE2 and (b) SARS-CoV-2···ACE2. All of the disulfide bridges between cysteine residues are shown in green van der Waals (vdW) spheres and thiol groups in cyan licorice.
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Figure 3
Figure 3. RMSDs, averaged over 1 ns MD simulation, of the protein complexes of ACE2 and SARS-CoV or SARS-CoV-2. Disulfide-containing proteins are referred to as oxidized with a shorthand notation of “ox”, while thiol variants are denoted with “red” notation.
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Figure 4
Figure 4. Change in residue-level RMSFs of C_α atoms in the oxidized and reduced protein complexes: (a) SARS-CoV···ACE2 and (b) SARS-CoV-2···ACE2. The cysteine residues, for each protein system (labeled in Figure 2), are highlighted as vdW spheres. The backbone as well as the cysteine residues are color-coded, large fluctuations are shown in red, and small fluctuations are in blue. The medium-scale fluctuations are shown in green.
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Figure 5
Figure 5. Comparison of the conformational change at the protein–protein interface in CoV^ox···ACE2^ox (left) and CoV^red···ACE2^red (right). CoV and ACE2 subunits in the complex are shown in blue and red colors, respectively, at the center. The structural motif containing the two helices of ACE2 and a β sheet of the CoV (or CoV-2) was monitored before (top) and after (bottom) 20 ns MD simulation. The left and right panels show the difference in conformational changes in the oxidized form (CoV^ox···ACE2^ox) and reduced form (CoV^red···ACE2^red), respectively.
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Scheme 1
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  Proceedings of the National Academy of Sciences of the United States of America (1994), 91 (10), 4559-63CODEN: PNASA6; ISSN:0027-8424.
  The cell surface of mammalian cells is capable of reductively cleaving disulfide bonds of exogenous membrane-bound macromols. (for instance, the interchain disulfide of diphtheria toxin), and inhibiting this process with membrane-impermeant sulfhydryl reagents prevents diphtheria toxin cytotoxicity. More recently it was found that the same membrane function can be inhibited by bacitracin, an inhibitor of protein disulfide-isomerase (PDI), and by monoclonal antibodies against PDI, suggesting that PDI catalyzes a thiol-disulfide interchange between its thiols and the disulfides of membrane-bound macromols. The authors provide evidence that the same reductive process plays a role in the penetration of membrane-bound human immunodeficiency virus (HIV) and show that HIV infection of human lymphoid cells is markedly inhibited by the membrane-impermeant sulfhydryl blocker 5,5'-dithiobis(2-nitrobenzoic acid), by bacitracin, and by anti-PDI antibodies. The results imply that HIV and its target cell engage in a thiol-disulfide interchange mediated by PDI and that the redn. of crit. disulfides in viral envelope glycoproteins may be the initial event that triggers conformational changes required for HIV entry and cell infection. These findings suggest addnl. approaches to impede cell infection by HIV.
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6. 6
  Gallina, A.; Hanley, T. M.; Mandel, R.; Trahey, M.; Broder, C. C.; Viglianti, G. A.; Ryser, H. J. Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J. Biol. Chem. 2002, 277, 50579– 50588, DOI: 10.1074/jbc.M204547200
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  6
  Inhibitors of Protein-Disulfide Isomerase Prevent Cleavage of Disulfide Bonds in Receptor-bound Glycoprotein 120 and Prevent HIV-1 Entry
  Gallina, Angelo; Hanley, Timothy M.; Mandel, Richard; Trahey, Meg; Broder, Christopher C.; Viglianti, Gregory A.; Ryser, Hugues J.-P.
  Journal of Biological Chemistry (2002), 277 (52), 50579-50588CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  We previously reported that monoclonal antibodies to protein-disulfide isomerase (PDI) and other membrane-impermeant PDI inhibitors prevented HIV-1 infection. PDI is present at the surface of HIV-1 target cells and reduces disulfide bonds in a model peptide attached to the cell membrane. Here we show that sol. PDI cleaves disulfide bonds in recombinant envelope glycoprotein gp120 and that gp120 bound to the surface receptor CD4 undergoes a disulfide redn. that is prevented by PDI inhibitors. Concns. of inhibitors that prevent this redn. and inhibit the cleavage of surface-bound disulfide conjugate prevent infection at the level of HIV-1 entry. The entry of HIV-1 strains differing in their coreceptor specificities is similarly inhibited, and so is the redn. of gp120 bound to CD4 of coreceptor-neg. cells. PDI inhibitors also prevent HIV envelope-mediated cell-cell fusion but have no effect on the entry of HIV-1 pseudo-typed with murine leukemia virus envelope. Importantly, PDI coppts. with both sol. and cellular CD4. We propose that a PDI·CD4 assocn. at the cell surface enables PDI to reach CD4-bound virus and to reduce disulfide bonds present in the domain of gp120 that binds to CD4. Conformational changes resulting from the opening of gp120-disulfide loops may drive the processes of virus-cell and cell-cell fusion. The biochem. events described identify new potential targets for anti-HIV agents.
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7. 7
  Lavillette, D.; Barbouche, R.; Yao, Y.; Boson, B.; Cosset, F. L.; Jones, I. M.; Fenouillet, E. Significant redox insensitivity of the functions of the SARS-CoV spike glycoprotein: comparison with HIV envelope. J. Biol. Chem. 2006, 281, 9200– 9204, DOI: 10.1074/jbc.M512529200
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  7
  Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein: Comparison with HIV envelope
  Lavillette, Dimitri; Barbouche, Rym; Yao, Yongxiu; Boson, Bertrand; Cosset, Francois-Loic; Jones, Ian M.; Fenouillet, Emmanuel
  Journal of Biological Chemistry (2006), 281 (14), 9200-9204CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  The capacity of the surface glycoproteins of enveloped viruses to mediate virus/cell binding and membrane fusion requires a proper thiol/disulfide balance. Chem. manipulation of their redox state using reducing agents or free sulfhydryl reagents affects virus/cell interaction. Conversely, natural thiol/disulfide rearrangements often occur during the cell interaction to trigger fusogenicity, hence the virus entry. We examd. the relationship between the redox state of the 20 cysteine residues of the SARS-CoV (severe acute respiratory syndrome coronavirus) Spike glycoprotein S1 subdomain and its functional properties. Mature S1 exhibited ∼4 unpaired cysteines, and chem. reduced S1 displaying up to ∼6 addnl. unpaired cysteines still bound ACE2 and enabled fusion. In addn., virus/cell membrane fusion occurred in the presence of sulfhydryl-blocking reagents and oxidoreductase inhibitors. Thus, in contrast to various viruses including HIV (human immunodeficiency virus) examd. in parallel, the functions of the SARS-CoV Spike glycoprotein exhibit a significant and surprising independence of redox state, which may contribute to the wide host range of the virus. These data suggest clues for molecularly engineering vaccine immunogens.
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8. 8
  Pan, S.; Chen, H. H.; Correia, C.; Dai, H.; Witt, T. A.; Kleppe, L. S.; Burnett, J. C., Jr.; Simari, R. D. Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate. PLoS One 2014, 9, e112986 DOI: 10.1371/journal.pone.0112986
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  8
  Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate
  Pan, Shuchong; Chen, Horng H.; Correia, Cristina; Dai, Haiming; Witt, Tyra A.; Kleppe, Laurel S.; Burnett, John C., Jr.; Simari, Robert D.
  PLoS One (2014), 9 (11), e112986/1-e112986/14, 14 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Rationale: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. Objective: We utilized complementary in vitro and in vivo models to det. the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. Methods and Results: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addn. of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochem. Conclusion: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors.
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9. 9
  Mathys, L.; Balzarini, J. The role of cellular oxidoreductases in viral entry and virus infection-associated oxidative stress: potential therapeutic applications. Expert Opin. Ther. Targets 2016, 20, 123– 143, DOI: 10.1517/14728222.2015.1068760
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  9
  The role of cellular oxidoreductases in viral entry and virus infection-associated oxidative stress: potential therapeutic applications
  Mathys, Leen; Balzarini, Jan
  Expert Opinion on Therapeutic Targets (2016), 20 (1), 123-143CODEN: EOTTAO; ISSN:1472-8222. (Taylor & Francis Ltd.)
  Cellular oxidoreductases catalyze thiol/disulfide exchange reactions in susceptible proteins and contribute to the cellular defense against oxidative stress. Oxidoreductases and oxidative stress are also involved in viral infections. In this overview, different aspects of the role of cellular oxidoreductases and oxidative stress during viral infections are discussed from a chemotherapeutic viewpoint. Entry of enveloped viruses into their target cells is triggered by the interaction of viral envelope glycoproteins with cellular (co)receptor(s) and depends on obligatory conformational changes in these viral envelope glycoproteins and/or cellular receptors. For some viruses, these conformational changes are mediated by cell surface-assocd. cellular oxidoreductases, which mediate disulfide bridge redns. in viral envelope glycoprotein(s). Therefore, targeting these oxidoreductases using oxidoreductase inhibitors might yield an interesting strategy to block viral entry of these viruses. Furthermore, since viral infections are often assocd. with systemic oxidative stress, contributing to disease progression, the enhancement of the cellular antioxidant defense systems might have potential as an adjuvant antiviral strategy, slowing down disease progression. Promising antiviral data were obtained for both strategies. However, potential pitfalls have also been identified for these strategies, indicating that it is important to carefully assess the benefits vs. risks of these antiviral strategies.
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10. 10
  Camini, F. C.; da Silva Caetano, C. C.; Almeida, L. T.; de Brito Magalhães, C. L. Implications of oxidative stress on viral pathogenesis. Arch. Virol. 2017, 162, 907– 917, DOI: 10.1007/s00705-016-3187-y
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  10
  Implications of oxidative stress on viral pathogenesis
  Camini, Fernanda Caetano; Caetano, Camila Carla da Silva; Almeida, Leticia Trindade; Magalhaes, Cintia Lopes de Brito
  Archives of Virology (2017), 162 (4), 907-917CODEN: ARVIDF; ISSN:0304-8608. (Springer-Verlag GmbH)
  Reactive species are frequently formed after viral infections. Antioxidant defences, including enzymic and non-enzymic components, protect against reactive species, but sometimes these defences are not completely adequate. An imbalance in the prodn. of reactive species and the body's inability to detoxify these reactive species is referred to as oxidative stress. The aim of this review is to analyze the role of oxidative stress in the pathogenesis of viral infections and highlight some major therapeutic approaches that have gained importance, with regards to controlling virus-induced oxidative injury. Attention will be focused on DNA viruses (papillomaviruses, hepadnaviruses), RNA viruses (flaviviruses, orthomyxoviruses, paramyxoviruses, togaviruses) and retroviruses (human immunodeficiency virus). In general, viruses cause an imbalance in the cellular redox environment, which depending on the virus and the cell can result in different responses, e.g. cell signaling, antioxidant defences, reactive species, and other processes. Therefore, the modulation of reactive species prodn. and oxidative stress potentially represents a novel pharmacol. approach for reducing the consequences of viral pathogenesis.
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11. 11
  Fenouillet, E.; Barbouche, R.; Jones, I. M. Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus. Antioxid. Redox Signaling 2007, 9, 1009– 1034, DOI: 10.1089/ars.2007.1639
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  11
  Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus
  Fenouillet, Emmanuel; Barbouche, Rym; Jones, Ian M.
  Antioxidants & Redox Signaling (2007), 9 (8), 1009-1034CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)
  A review. For enveloped viruses, genome entry into the target cell involves two major steps: virion binding to the cell-surface receptor and fusion of the virion and cell membranes. Virus-cell membrane fusion is mediated by the virus envelope complex, and its fusogenicity is the result of an active virus-cell interaction process that induces conformation changes within the envelope. For some viruses, such as influenza, exposure to an acidic milieu within the cell during the early steps of infection triggers the necessary structural changes. However, for other pathogens which are not exposed to such environmental stress, activation of fusogenicity can result from precise thiol/disulfide rearrangements mediated by either an endogenous redox autocatalytic isomerase or a cell-assocd. oxidoreductase. Study of the activation of HIV envelope fusogenicity has revealed new knowledge about how redox changes within a viral envelope trigger fusion. We discuss these findings and their implication for anti-HIV therapy. In addn., to compare and contrast the situation outlined for HIV with an enveloped virus that can fuse with the cell plasma membrane independent of the redox status of its envelope protein, we review parallel data obtained on SARS coronavirus entry.
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12. 12
  Yi, M. C.; Khosla, C. Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment. Annu. Rev. Chem. Biomol. Eng. 2016, 7, 197– 222, DOI: 10.1146/annurev-chembioeng-080615-033553
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  12
  Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment
  Yi, Michael C.; Khosla, Chaitan
  Annual Review of Chemical and Biomolecular Engineering (2016), 7 (), 197-222CODEN: ARCBCY; ISSN:1947-5438. (Annual Reviews)
  Disulfide bonds represent versatile posttranslational modifications whose roles encompass the structure, catalysis, and regulation of protein function. Due to the oxidizing nature of the extracellular environment, disulfide bonds found in secreted proteins were once believed to be inert. This notion has been challenged by the discovery of redox-sensitive disulfides that, once cleaved, can lead to changes in protein activity. These functional disulfides are twisted into unique configurations, leading to high strain and potential energy. In some cases, cleavage of these disulfides can lead to a gain of function in protein activity. Thus, these motifs can be referred to as switches. We describe the couples that control redox in the extracellular environment, examine several examples of proteins with switchable disulfides, and discuss the potential applications of disulfides in mol. biol.
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13. 13
  Li, F. Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. J. Virol. 2008, 82, 6984– 6991, DOI: 10.1128/JVI.00442-08
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  13
  Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections
  Li, Fang
  Journal of Virology (2008), 82 (14), 6984-6991CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
  It is believed that a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), was passed from palm civets to humans and caused the epidemic of SARS in 2002 to 2003. The major species barriers between humans and civets for SARS-CoV infections are the specific interactions between a defined receptor-binding domain (RBD) on a viral spike protein and its host receptor, angiotensin-converting enzyme 2 (ACE2). In this study a chimeric ACE2 bearing the crit. N-terminal helix from civet and the remaining peptidase domain from human was constructed, and it was shown that this construct has the same receptor activity as civet ACE2. In addn., crystal structures of the chimeric ACE2 complexed with RBDs from various human and civet SARS-CoV strains were detd. These structures, combined with a previously detd. structure of human ACE2 complexed with the RBD from a human SARS-CoV strain, have revealed a structural basis for understanding the major species barriers between humans and civets for SARS-CoV infections. They show that the major species barriers are detd. by interactions between four ACE2 residues (residues 31, 35, 38, and 353) and two RBD residues (residues 479 and 487), that early civet SARS-CoV isolates were prevented from infecting human cells due to imbalanced salt bridges at the hydrophobic virus/receptor interface, and that SARS-CoV has evolved to gain sustained infectivity for human cells by eliminating unfavorable free charges at the interface through stepwise mutations at positions 479 and 487. These results enhance our understanding of host adaptations and cross-species infections of SARS-CoV and other emerging animal viruses.
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14. 14
  Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C. L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020, 367, 1260– 1263, DOI: 10.1126/science.abb2507
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  14
  Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
  Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.
  Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
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15. 15
  Wang, Q.; Zhang, Y.; Wu, L.; Niu, S.; Song, C.; Zhang, Z.; Lu, G.; Qiao, C.; Hu, Y.; Yuen, K. Y.; Wang, Q.; Zhou, H.; Yan, J.; Qi, J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 2020, 181, 894– 904.e9, DOI: 10.1016/j.cell.2020.03.045
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  15
  Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2
  Wang, Qihui; Zhang, Yanfang; Wu, Lili; Niu, Sheng; Song, Chunli; Zhang, Zengyuan; Lu, Guangwen; Qiao, Chengpeng; Hu, Yu; Yuen, Kwok-Yung; Wang, Qisheng; Zhou, Huan; Yan, Jinghua; Qi, Jianxun
  Cell (Cambridge, MA, United States) (2020), 181 (4), 894-904.e9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that obsd. for SARS-CoV. However, at. details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Addnl., a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
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16. 16
  Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020, 367, 1444– 1448, DOI: 10.1126/science.abb2762
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  16
  Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
  Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang
  Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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17. 17
  Adams, L. M.; Andrews, R. J.; Hu, Q. H.; Schmit, H. L.; Hati, S.; Bhattacharyya, S. Crowder-Induced Conformational Ensemble Shift in Escherichia coli Prolyl-tRNA Synthetase. Biophys. J. 2019, 117, 1269– 1284, DOI: 10.1016/j.bpj.2019.08.033
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  17
  Crowder-Induced Conformational Ensemble Shift in Escherichia coli Prolyl-tRNA Synthetase
  Adams, Lauren M.; Andrews, Ryan J.; Hu, Quin H.; Schmit, Heidi L.; Hati, Sanchita; Bhattacharyya, Sudeep
  Biophysical Journal (2019), 117 (7), 1269-1284CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
  The effect of mol. crowding on the structure and function of Escherichia coli prolyl-tRNA synthetase (Ec ProRS), a member of the aminoacyl-tRNA synthetase family, has been investigated using a combined exptl. and theor. method. Ec ProRS is a multidomain enzyme; coupled-domain dynamics are essential for efficient catalysis. To gain insight into the mechanistic detail of the crowding effect, kinetic studies were conducted with varying concns. and sizes of crowders. In parallel, spectroscopic and quantum chem. studies were employed to probe the "soft interactions" between crowders and protein side chains. Finally, the dynamics of the dimeric protein was examd. in the presence of crowders using a long-duration (70 ns) classical mol. dynamic simulations. The results of the simulations revealed a shift in the conformational ensemble, which is consistent with the preferential exclusion of cosolutes. The "soft interactions" model of the crowding effect also explained the alteration in kinetic parameters. In summary, the study found that the effects of mol. crowding on both conformational dynamics and catalytic function are correlated in the multidomain Ec ProRS, an enzyme that is central to protein synthesis in all living cells. This study affirmed that large and small cosolutes have considerable impacts on the structure, dynamics, and function of modular proteins and therefore must be considered for stabilizing protein-based pharmaceuticals and industrial enzymes.
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18. 18
  Bechtel, T. J.; Weerapana, E. From structure to redox: The diverse functional roles of disulfides and implications in disease. Proteomics 2017, 17, 1600391 DOI: 10.1002/pmic.201600391
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19. 19
  Ballatori, N.; Krance, S. M.; Marchan, R.; Hammond, C. L. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol. Aspects Med. 2009, 30, 13– 28, DOI: 10.1016/j.mam.2008.08.004
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  Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology
  Ballatori, Nazzareno; Krance, Suzanne M.; Marchan, Rosemarie; Hammond, Christine L.
  Molecular Aspects of Medicine (2009), 30 (1-2), 13-28CODEN: MAMED5; ISSN:0098-2997. (Elsevier B.V.)
  A review. Reduced glutathione (GSH) is crit. for many cellular processes, and both its intracellular and extracellular concns. are tightly regulated. Intracellular GSH levels are regulated by two main mechanisms: by adjusting the rates of synthesis and of export from cells. Some of the proteins responsible for GSH export from mammalian cells have recently been identified, and there is increasing evidence that these GSH exporters are multispecific and multifunctional, regulating a no. of key biol. processes. In particular, some of the multidrug resistance-assocd. proteins (Mrp/Abcc) appear to mediate GSH export and homeostasis. The Mrp proteins mediate not only GSH efflux, but they also export oxidized glutathione derivs. (e.g., glutathione disulfide (GSSG), S-nitrosoglutathione (GS-NO), and glutathione-metal complexes), as well as other glutathione S-conjugates. The ability to export both GSH and oxidized derivs. of GSH, endows these transporters with the capacity to directly regulate the cellular thiol-redox status, and therefore the ability to influence many key signaling and biochem. pathways. Among the many processes that are influenced by the GSH transporters are apoptosis, cell proliferation, and cell differentiation. This report summarizes the evidence that Mrps contribute to the regulation of cellular GSH levels and the thiol-redox state, and thus to the many biochem. processes that are influenced by this tripeptide.
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20. 20
  Xia, H.; Suda, S.; Bindom, S.; Feng, Y.; Gurley, S. B.; Seth, D.; Navar, L. G.; Lazartigues, E. ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS One 2011, 6, e22682 DOI: 10.1371/journal.pone.0022682
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  ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function
  Xia, Huijing; Suda, Sonia; Bindom, Sharell; Feng, Yumei; Gurley, Susan B.; Seth, Dale; Navar, L. Gabriel; Lazartigues, Eric
  PLoS One (2011), 6 (7), e22682CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a redn. of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2-/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 wk). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2-/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2-/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2-/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also obsd. on baseline in mature ACE2-/y mice (48 wk). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2-/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-assocd. dysautonomia and oxidative stress.
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21. 21
  Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graphics 1996, 14, 33– 38, DOI: 10.1016/0263-7855(96)00018-5
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  VDM: visual molecular dynamics
  Humphrey, William; Dalke, Andrew; Schulten, Klaus
  Journal of Molecular Graphics (1996), 14 (1), 33-8, plates, 27-28CODEN: JMGRDV; ISSN:0263-7855. (Elsevier)
  VMD is a mol. graphics program designed for the display and anal. of mol. assemblies, in particular, biopolymers such as proteins and nucleic acids. VMD can simultaneously display any no. of structures using a wide variety of rendering styles and coloring methods. Mols. are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resoln. raster images of displayed mols. may be produced by generating input scripts for use by a no. of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate mol. dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biol., which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs, VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
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22. 22
  Guvench, O.; Hatcher, E.; Venable, R. M.; Pastor, R. W.; MacKerell, A. D. CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses. J. Chem. Theory Comput. 2009, 5, 2353– 2370, DOI: 10.1021/ct900242e
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  22
  CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses
  Guvench, Olgun; Hatcher, Elizabeth; Venable, Richard M.; Pastor, Richard W.; MacKerell, Alexander D., Jr.
  Journal of Chemical Theory and Computation (2009), 5 (9), 2353-2370CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
  We present an extension of the CHARMM hexopyranose monosaccharide additive all-atom force field to enable modeling of glycosidic-linked hexopyranose polysaccharides. The new force field parameters encompass 1-1, 1-2, 1-3, 1-4, and 1-6 hexopyranose glycosidic linkages, as well as O-methylation at the C1 anomeric carbon, and are developed to be consistent with the CHARMM all-atom biomol. force fields for proteins, nucleic acids, and lipids. The parameters are developed in a hierarchical fashion using model compds. contg. the key atoms in the full carbohydrates, in particular O-methyl-tetrahydropyran and glycosidic-linked dimers consisting of two mols. of tetrahyropyran or one mol. of tetrahydropyran and one of cyclohexane. Target data for parameter optimization include full two-dimensional energy surfaces defined by the Φ/Ψ glycosidic dihedral angles in the disaccharide analogs, as detd. by quantum mech. MP2/cc-pVTZ single point energies on MP2/6-31G(d) optimized structures (MP2/cc-pVTZ//MP2/6-31G(d)). In order to achieve balanced, transferable dihedral parameters for the Φ/Ψ glycosidic dihedral angles, surfaces for all possible chiralities at the ring carbon atoms involved in the glycosidic linkages are considered, resulting in over 5000 MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. Also included as target data are vibrational frequencies, pair interaction energies and distances with water mols., and intramol. geometries including distortion of the glycosidic valence angle as a function of the glycosidic dihedral angles. The model compd. optimized force field parameters are validated on full disaccharides through the comparison of mol. dynamics results to available exptl. data. Good agreement is achieved with expt. for a variety of properties including crystal cell parameters and intramol. geometries, aq. densities, and aq. NMR coupling consts. assocd. with the glycosidic linkage. The newly developed parameters allow for the modeling of linear, branched, and cyclic hexopyranose glycosides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing CHARMM biomol. force fields.
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23. 23
  Raman, E. P.; Guvench, O.; MacKerell, A. D., Jr. CHARMM additive all-atom force field for glycosidic linkages in carbohydrates involving furanoses. J. Phys. Chem. B 2010, 114, 12981– 12994, DOI: 10.1021/jp105758h
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  23
  CHARMM Additive All-Atom Force Field for Glycosidic Linkages in Carbohydrates Involving Furanoses
  Raman, E. Prabhu; Guvench, Olgun; MacKerell, Alexander D., Jr.
  Journal of Physical Chemistry B (2010), 114 (40), 12981-12994CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
  Presented is an extension of the CHARMM additive carbohydrate all-atom force field to enable modeling of polysaccharides contg. furanose sugars. The new force field parameters encompass 1 ↔ 2, 1 → 3, 1 → 4, and 1 → 6 pyranose-furanose linkages and 2 → 1 and 2 → 6 furanose-furanose linkages, building on existing hexopyranose and furanose monosaccharide parameters. The model compds. were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and THF as to contain the key atoms in full carbohydrates. Target data for optimization included two-dimensional quantum mech. (QM) potential energy scans of the Φ/Ψ glycosidic dihedral angles, with geometry optimization at the MP2/6-31G(d) level followed by MP2/cc-pVTZ single-point energies. All possible chiralities of the model compds. at the linkage carbons were considered, and for each geometry, the THF ring was constrained to the favorable south or north conformations. Target data also included QM vibrational frequencies and pair interaction energies and distances with water mols. Force field validation included comparison of computed crystal properties, aq. soln. densities, and NMR J-coupling consts. to exptl. ref. values. Simulations of infinite crystals showed good agreement with exptl. values for intramol. geometries as well as for crystal unit cell parameters. Addnl., aq. soln. densities and available NMR data were reproduced to a high degree of accuracy, thus validating the hierarchically optimized parameters in both cryst. and aq. condensed phases. The newly developed parameters allow for the modeling of linear, branched, and cyclic pyranose/furanose polysaccharides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing additive CHARMM biomol. force fields.
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24. 24
  Guvench, O.; Mallajosyula, S. S.; Raman, E. P.; Hatcher, E.; Vanommeslaeghe, K.; Foster, T. J.; Jamison, F. W., II; Mackerell, A. D., Jr. CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling. J. Chem. Theory Comput. 2011, 7, 3162– 3180, DOI: 10.1021/ct200328p
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  24
  CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate-Protein Modeling
  Guvench, Olgun; Mallajosyula, Sairam S.; Raman, E. Prabhu; Hatcher, Elizabeth; Vanommeslaeghe, Kenno; Foster, Theresa J.; Jamison, Francis W.; MacKerell, Alexander D.
  Journal of Chemical Theory and Computation (2011), 7 (10), 3162-3180CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
  Monosaccharide derivs. such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details the development of force-field parameters for these monosaccharides and their covalent connections to proteins via O linkages to serine or threonine side chains and via N linkages to asparagine side chains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small mols. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the mol. simulation of a wide variety of biol. important mols. such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mech. (QM) geometries and conformational energies of model compds., as well as to QM pair interaction energies and distances of model compds. with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallog. data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomol. force field, they further broaden the types of heterogeneous systems accessible with a consistently developed force-field model.
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25. 25
  Best, R. B.; Zhu, X.; Shim, J.; Lopes, P. E. M.; Mittal, J.; Feig, M.; MacKerell, A. D. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. J. Chem. Theory Comput. 2012, 8, 3257– 3273, DOI: 10.1021/ct300400x
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  25
  Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone .vphi., ψ and Side-Chain χ1 and χ2 Dihedral Angles
  Best, Robert B.; Zhu, Xiao; Shim, Jihyun; Lopes, Pedro E. M.; Mittal, Jeetain; Feig, Michael; MacKerell, Alexander D.
  Journal of Chemical Theory and Computation (2012), 8 (9), 3257-3273CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
  While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large no. of applications, limitations in the model with respect to the equil. between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non-Gly, -Pro) backbone CMAP potential has been refined against exptl. soln. NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mech. energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mech. energy surfaces, followed by addnl. empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against a collection of exptl. data: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equil. folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for modeling and simulation studies of proteins, including studies of protein folding, assembly, and functionally relevant conformational changes.
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26. 26
  Mallajosyula, S. S.; Guvench, O.; Hatcher, E.; Mackerell, A. D., Jr. CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates. J. Chem. Theory Comput. 2012, 8, 759– 776, DOI: 10.1021/ct200792v
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  26
  CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates
  Mallajosyula, Sairam S.; Guvench, Olgun; Hatcher, Elizabeth; MacKerell, Alexander D.
  Journal of Chemical Theory and Computation (2012), 8 (2), 759-776CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
  Presented is an extension of the CHARMM additive all-atom carbohydrate force field to enable the modeling of phosphate and sulfate linked to carbohydrates. The parameters are developed in a hierarchical fashion using model compds. contg. the key atoms in the full carbohydrates. Target data for parameter optimization included full two-dimensional energy surfaces defined by the glycosidic dihedral angle pairs in the phosphate/sulfate model compd. analogs of hexopyranose monosaccharide phosphates and sulfates, as detd. by quantum mech. (QM) MP2/cc-pVTZ single point energies on MP2/6-31+G(d) optimized structures. To achieve balanced, transferable dihedral parameters for the dihedral angles, surfaces for all possible anomeric and conformational states were included during the parametrization process. To model physiol. relevant systems, both the mono- and dianionic charged states were studied for the phosphates. This resulted in over 7000 MP2/cc-pVTZ//MP2/6-31G+(d) model compd. conformational energies which, supplemented with QM geometries, were the main target data for the parametrization. Parameters were validated against crystals of relevant monosaccharide derivs. obtained from the Cambridge Structural Database (CSD) and larger systems, inositol-(tri/tetra/penta) phosphates noncovalently bound to the pleckstrin homol. (PH) domain and oligomeric chondroitin sulfate in soln. and in complex with cathepsin K protein.
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27. 27
  Essmann, U.; Perera, L.; Berkowitz, M. L. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577, DOI: 10.1063/1.470117
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  A smooth particle mesh Ewald method
  Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.; Darden, Tom; Lee, Hsing; Pedersen, Lee G.
  Journal of Chemical Physics (1995), 103 (19), 8577-93CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
  The previously developed particle mesh Ewald method is reformulated in terms of efficient B-spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p ≥ 1. Furthermore, efficient calcn. of the virial tensor follows. Use of B-splines in the place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. The authors demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomol. systems with many thousands of atoms and this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 Å or less.
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28. 28
  Jurrus, E.; Engel, D.; Star, K.; Monson, K.; Brandi, J.; Felberg, L. E.; Brookes, D. H.; Wilson, L.; Chen, J.; Liles, K.; Chun, M.; Li, P.; Gohara, D. W.; Dolinsky, T.; Konecny, R.; Koes, D. R.; Nielsen, J. E.; Head-Gordon, T.; Geng, W.; Krasny, R.; Wei, G. W.; Holst, M. J.; McCammon, J. A.; Baker, N. A. Improvements to the APBS biomolecular solvation software suite. Protein Sci. 2018, 27, 112– 128, DOI: 10.1002/pro.3280
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  Improvements to the APBS biomolecular solvation software suite
  Jurrus, Elizabeth; Engel, Dave; Star, Keith; Monson, Kyle; Brandi, Juan; Felberg, Lisa E.; Brookes, David H.; Wilson, Leighton; Chen, Jiahui; Liles, Karina; Chun, Minju; Li, Peter; Gohara, David W.; Dolinsky, Todd; Konecny, Robert; Koes, David R.; Nielsen, Jens Erik; Head-Gordon, Teresa; Geng, Weihua; Krasny, Robert; Wei, Guo-Wei; Holst, Michael J.; McCammon, J. Andrew; Baker, Nathan A.
  Protein Science (2018), 27 (1), 112-128CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
  The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomol. assemblages that have provided impact in the study of a broad range of chem., biol., and biomedical applications. APBS addresses the three key technol. challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomol. solvation and electrostatics, robust and scalable software for applying those theories to biomol. systems, and mechanisms for sharing and analyzing biomol. electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson-Boltzmann anal. and a semi-anal. solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory-based algorithm for detg. pKa values, and an improved web-based visualization tool for viewing electrostatics.
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29. 29
  Dolinsky, T. J.; Czodrowski, P.; Li, H.; Nielsen, J. E.; Jensen, J. H.; Klebe, G.; Baker, N. A. PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations. Nucleic Acids Res. 2007, 35, W522– W525, DOI: 10.1093/nar/gkm276
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  PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations
  Dolinsky Todd J; Czodrowski Paul; Li Hui; Nielsen Jens E; Jensen Jan H; Klebe Gerhard; Baker Nathan A
  Nucleic acids research (2007), 35 (Web Server issue), W522-5 ISSN:.
  Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pK(a) values, binding constants of ligands, and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systems- and genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665-W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pK(a) estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http://pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization.
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30. 30
  Johnson, J. M.; Sanford, B. L.; Strom, A. M.; Tadayon, S. N.; Lehman, B. P.; Zirbes, A. M.; Bhattacharyya, S.; Musier-Forsyth, K.; Hati, S. Multiple pathways promote dynamical coupling between catalytic domains in Escherichia coli prolyl-tRNA synthetase. Biochemistry 2013, 52, 4399– 4412, DOI: 10.1021/bi400079h
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  Multiple Pathways Promote Dynamical Coupling between Catalytic Domains in Escherichia coli Prolyl-tRNA Synthetase
  Johnson, James M.; Sanford, Brianne L.; Strom, Alexander M.; Tadayon, Stephanie N.; Lehman, Brent P.; Zirbes, Arrianna M.; Bhattacharyya, Sudeep; Musier-Forsyth, Karin; Hati, Sanchita
  Biochemistry (2013), 52 (25), 4399-4412CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Aminoacyl-tRNA synthetases are multidomain enzymes that catalyze covalent attachment of amino acids to their cognate tRNA. Cross-talk between functional domains is a prerequisite for this process. In this study, we investigate the mol. mechanism of site-to-site communication in Escherichia coli prolyl-tRNA synthetase (Ec ProRS). Earlier studies have demonstrated that evolutionarily conserved and/or co-evolved residues that are engaged in correlated motion are crit. for the propagation of functional conformational changes from one site to another in modular proteins. Here, mol. simulation and bioinformatics-based anal. were performed to identify dynamically coupled and evolutionarily constrained residues that form contiguous pathways of residue-residue interactions between the aminoacylation and editing domains of Ec ProRS. The results of this study suggest that multiple pathways exist between these two domains to maintain the dynamic coupling essential for enzyme function. Moreover, residues in these interaction networks are generally highly conserved. Site-directed changes of on-pathway residues have a significant impact on enzyme function and dynamics, suggesting that any perturbation along these pathways disrupts the native residue-residue interactions that are required for effective communication between the two functional domains. Free energy anal. revealed that communication between residues within a pathway and cross-talk between pathways are important for coordinating functions of different domains of Ec ProRS for efficient catalysis.
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31. 31
  Verlet, L. Computer “experiments” on classic fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys. Rev. 1967, 159, 98– 103, DOI: 10.1103/PhysRev.159.98
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  Computer "experiments" on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules
  Verlet, Loup
  Physical Review (1967), 159 (1), 98-103CODEN: PHRVAO; ISSN:0031-899X.
  The equation of motion of a system of 864 particles interacting through a Lennard-Jones potential was integrated for various values of the temp. and d., relative, generally, to a fluid state. The equil. properties agree with the corresponding properties of Ar. The equil. state of Ar can be described through a 2-body potential.
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32. 32
  Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kalé, L.; Schulten, K. Scalable molecular dynamics with NAMD. J. Comput. Chem. 2005, 26, 1781– 1802, DOI: 10.1002/jcc.20289
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  Scalable molecular dynamics with NAMD
  Phillips, James C.; Braun, Rosemary; Wang, Wei; Gumbart, James; Tajkhorshid, Emad; Villa, Elizabeth; Chipot, Christophe; Skeel, Robert D.; Kale, Laxmikant; Schulten, Klaus
  Journal of Computational Chemistry (2005), 26 (16), 1781-1802CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
  NAMD is a parallel mol. dynamics code designed for high-performance simulation of large biomol. systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical mol. dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temp. and pressure controls used. Features for steering the simulation across barriers and for calcg. both alchem. and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomol. system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the mol. graphics/sequence anal. software VMD and the grid computing/collab. software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
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33. 33
  Geng, W.; Krasny, R. A treecode-accelerated boundary integral Poisson–Boltzmann solver for electrostatics of solvated biomolecules. J. Comput. Phys. 2013, 247, 62– 78, DOI: 10.1016/j.jcp.2013.03.056
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  A treecode-accelerated boundary integral Poisson-Boltzmann solver for electrostatics of solvated biomolecules
  Geng, Weihua; Krasny, Robert
  Journal of Computational Physics (2013), 247 (), 62-78CODEN: JCTPAH; ISSN:0021-9991. (Elsevier Inc.)
  We present a treecode-accelerated boundary integral (TABI) solver for electrostatics of solvated biomols. described by the linear Poisson-Boltzmann equation. The method employs a well-conditioned boundary integral formulation for the electrostatic potential and its normal deriv. on the mol. surface. The surface is triangulated and the integral equations are discretized by centroid collocation. The linear system is solved by GMRES iteration and the matrix-vector product is carried out by a Cartesian treecode which reduces the cost from O(N2) to O(NlogN), where N is the no. of faces in the triangulation. The TABI solver is applied to compute the electrostatic solvation energy in two cases, the Kirkwood sphere and a solvated protein. We present the error, CPU time, and memory usage, and compare results for the Poisson-Boltzmann and Poisson equations. We show that the treecode approxn. error can be made smaller than the discretization error, and we compare two versions of the treecode, one with uniform clusters and one with non-uniform clusters adapted to the mol. surface. For the protein test case, we compare TABI results with those obtained using the grid-based APBS code, and we also present parallel TABI simulations using up to eight processors. We find that the TABI solver exhibits good serial and parallel performance combined with relatively simple implementation, efficient memory usage, and geometric adaptability.
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34. 34
  Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215– 220, DOI: 10.1038/s41586-020-2180-5
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  Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
  Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong; Zhang, Qi; Shi, Xuanling; Wang, Qisheng; Zhang, Linqi; Wang, Xinquan
  Nature (London, United Kingdom) (2020), 581 (7807), 215-220CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
  Abstr.: A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from Dec. 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an at. level, we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural anal. identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analyzed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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  Madeira, F.; Park, Y. M.; Lee, J.; Buso, N.; Gur, T.; Madhusoodanan, N.; Basutkar, P.; Tivey, A. R. N.; Potter, S. C.; Finn, R. D.; Lopez, R. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 2019, 47, W636– W641, DOI: 10.1093/nar/gkz268
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  35
  The EMBL-EBI search and sequence analysis tools APIs in 2019
  Madeira, Fabio; Park, Young Mi; Lee, Joon; Buso, Nicola; Gur, Tamer; Madhusoodanan, Nandana; Basutkar, Prasad; Tivey, Adrian R. N.; Potter, Simon C.; Finn, Robert D.; Lopez, Rodrigo
  Nucleic Acids Research (2019), 47 (W1), W636-W641CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
  The EMBL-EBI provides free access to popular bioinformatics sequence anal. applications as well as to a full-featured text search engine with powerful cross-referencing and data retrieval capabilities. Access to these services is provided via user-friendly web interfaces and via established RESTful and SOAP Web Services APIs (https://www.ebi.ac.uk/seqdb/confluence/display/JDSAT/EMBL-EBI+Web+Services+APIs+-+Data+Retrieval). Both systems have been developed with the same core principles that allow them to integrate an ever-increasing vol. of biol. data, making them an integral part of many popular data resources provided at the EMBL-EBI. Here, we describe the latest improvements made to the frameworks which enhance the interconnectivity between public EMBL-EBI resources and ultimately enhance biol. data discoverability, accessibility, interoperability and reusability.
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Impact of Thiol–Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor

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Abstract

1. Introduction

2. Results and Discussion

Figure 1

Figure 2

2.1. Structural Changes along the Trajectory

Figure 3

2.2. Thermal Fluctuations due to the Cleavage of Disulfide Bridges

Figure 4

2.3. Binding Study

2.4. Molecular Basis of the Impaired Binding

Figure 5

3. Conclusions

4. Methodology

4.1. Computational Setup

4.2. Molecular Dynamics Simulations

4.3. Binding Free Energy Calculations

Scheme 1

Author Information

Acknowledgments

Abbreviations Used

References

Cited By

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Scheme 1

References

STEP 1:

STEP 2: