Critical Differences between the Binding Features of the Spike Proteins of SARS-CoV-2 and SARS-CoV

Bai, Chen; Warshel, Arieh

doi:10.1021/acs.jpcb.0c04317

Cited by 63 publications

(90 citation statements)

References 31 publications

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“…This is consistent with the above observation based on the pairs of residues at the interfaces (Figure 2b and Supplementary Figure S2). To this end, even though we observed distinguishable features of the interactions modeled by the two FFs, one similarity stands out clear: the RBD2-ACE2 interface has stronger interaction energies than the RBD1-ACE2 interface as concluded in previous studies, [2][3][4][5]8,[10][11][12][13]30 which results in more stable pairs of interacting residues in the RBD2-ACE2 interface than the RBD1-ACE2 interface as observed in Figure 2. Particularly for RBD1-ACE2 complex, both FFs apparently yield a meta-stable state, which is not evident in the RBD2-ACE2 complex.…”

Section: Energetics Of Rbd2-ace2 Vs Rbd1-ace2 Interfacessupporting

confidence: 63%

“…To the best of our knowledge, such a complete ranking has not been reported in previous studies, even though calculations of relative changes of interaction energies or free-energies were done for some of the pairs and mutations. 12,13 Figure 2a-b shows that both interfaces have almost the same number of interacting pairs. However, if counting stable pairs that have probability larger than 60% (i.e., in close contact 60% of the total simulation time), there are only 22 ± 2 pairs in RBD1-ACE2 interface, while RBD2-ACE2 showed substantially higher, 35 ± 1 stable pairs at the interface.…”

Section: Key Residues At Rbd2-ace2 Interfacementioning

confidence: 98%

“…This DDGMD (= DG2 -DG1) is almost three times the value estimated by a coarse-grain model (4.3 kcal/mol) in a recently published work. 12 This discrepancy may largely come from the simulated parameters (or FFs). It should be noted that DDGMD was computed without a thorough sampling of relative rotational and conformational dynamics of the RBDs and ACE2.…”

Section: Potential Of Mean Force (Pmf)mentioning

confidence: 99%

“…2 Freeenergy calculations were also done for the mutations at these residues to compare how they contribute to overall binding affinities via a coarse grain model. 12 Using homology models for comparing the structures of Bat-CoV, SARS-CoV, and SARS-CoV-2, Ortega et. al.…”

Section: Introductionmentioning

confidence: 99%

“…However, how these residues change the conformations at the RBD2-ACE2 interface in comparison to the RBD1-ACE2 interface remains to be elucidated. Even though free-energy calculations 12 reveal relatively important levels of these residues at RBD2-ACE2 interface, how they dynamically co-operate to enhance the binding of RBD2 and how RBD2 may dynamically dissociate from ACE2 have not yet been explored.…”

Section: Introductionmentioning

confidence: 99%

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Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction

Ngo

Jha

2020

Preprint

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SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS- CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in reduced dissociation rate of SARS-CoV-2 from human recep- tor protein compared to SARS-CoV. This phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study shed light on the key residues and their dynamics at the virus spike and human receptor binding interface and advance our knowledge for the development of diagnostics and therapeutics to combat the pandemic efficiently.

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Section: Energetics Of Rbd2-ace2 Vs Rbd1-ace2 Interfacessupporting

confidence: 63%

Section: Key Residues At Rbd2-ace2 Interfacementioning

confidence: 98%

Section: Potential Of Mean Force (Pmf)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction

Ngo

Jha

2020

Preprint

View full text Add to dashboard Cite

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Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Yamaçli

Avcı

2022

Advcd Theory and Sims

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The receptor binding domain (RBD) of SARS‐CoV‐2 binds to human ACE2 leading to infection. In this study, the complexes that are formed by the attachment of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are investigated via density functional theory (DFT) simulations to obtain binding energies. The DFT computations are performed without fragmenting the interfaces to involve longer‐range interactions for improved accuracy, which is one of the primary features of the approach used in this study. Basis set superposition error corrections and van der Waals dispersions are also included in the DFT simulations. The binding energies of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are computed as −4.76, −6.68, and −11.77 eV, respectively. These binding energy values indicate that the binding of the omicron variant to the ACE2 is much more favorable than the binding of the original strain and the delta variant, which constitute a molecular reason for the takeover of the omicron variant. The binding energies and the decomposition of these energies found in this study are expected to aid in the development of neutralizing agents.

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Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

An,

Yang,

Luo

et al. 2024

Proteins

Self Cite

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The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID‐19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike–angiotensin‐converting enzyme‐2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse‐grained model. Our study extended beyond the receptor‐binding domain (RBD) of spike trimer through comprehensive modeling of the full‐length spike trimer rather than just the RBD. Our free‐energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full‐length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

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Critical Differences between the Binding Features of the Spike Proteins of SARS-CoV-2 and SARS-CoV

Cited by 63 publications

References 31 publications

Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction

Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

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