Origin of the tight binding mode to ACE2 triggered by multi-point mutations in the omicron variant: a dynamic insight

Zhao, Xiaoyu; Xiong, Danyang; Luo, Song; Duan, Lili

doi:10.1039/d2cp00449f

Cited by 11 publications

(11 citation statements)

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“…A configurational change with a better packing of the N-terminal chain of ACE2 in comparison to that of the WT has been observed and could thermodynamically favor intermolecular interactions. 65 Such discrepancy with the WT strain dictated the choice of using the experimental X-ray structure of the BA.2 subvariant deposited in the PDB ( 7ZF7 ). 66 …”

Section: Methodsmentioning

confidence: 99%

“…The Omicron BA.2 variant differs significantly from its fellow VOCs and contains 16 mutations in its RBD alone (G333D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, and Y505H). A configurational change with a better packing of the N-terminal chain of ACE2 in comparison to that of the WT has been observed and could thermodynamically favor intermolecular interactions . Such discrepancy with the WT strain dictated the choice of using the experimental X-ray structure of the BA.2 subvariant deposited in the PDB (7ZF7).…”

Section: Methodsmentioning

confidence: 99%

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When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Lacam

Blazhynska

Chen

et al. 2022

J. Chem. Theory Comput.

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Accurate determination of binding free energy is pivotal for the study of many biological processes and has been applied in a number of theoretical investigations to compare the affinity of severe acute respiratory syndrome coronavirus 2 variants toward the host cell. Diversity of these variants challenges the development of effective general therapies, their transmissibility relying either on an increased affinity toward their dedicated human receptor, the angiotensin-converting enzyme 2 (ACE2), or on escaping the immune response. Now that robust structural data are available, we have determined with utmost accuracy the standard binding free energy of the receptor-binding domain to the most widespread variants, namely, Alpha, Beta, Delta, and Omicron BA.2, as well as the wild type (WT) in complex either with ACE2 or with antibodies, namely, S2E12 and H11-D4, using a rigorous theoretical framework that combines molecular dynamics and potential-of-mean-force calculations. Our results show that an appropriate starting structure is crucial to ensure appropriate reproduction of the binding affinity, allowing the variants to be compared. They also emphasize the necessity to apply the relevant methodology, bereft of any shortcut, to account for all the contributions to the standard binding free energy. Our estimates of the binding affinities support the view that while the Alpha and Beta variants lean on an increased affinity toward the host cell, the Delta and Omicron BA.2 variants choose immune escape. Moreover, the S2E12 antibody, already known to be active against the WT (Starr et al., 2021; Mlcochova et al., 2021), proved to be equally effective against the Delta variant. In stark contrast, H11-D4 retains a low affinity toward the WT compared to that of ACE2 for the latter. Assuming robust structural information, the methodology employed herein successfully addresses the challenging protein–protein binding problem in the context of coronavirus disease 2019 while offering promising perspectives for predictive studies of ever-emerging variants.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Lacam

Blazhynska

Chen

et al. 2022

J. Chem. Theory Comput.

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“…MD-based computational efforts evaluated the effect of omicron's mutations on ACE2 binding strength, [118,122,123] suggesting that YG339D, N440K, S477N, T478K, Q493K, N501Y increase the binding affinity, as also reported by Socher et al [124] S371L, S373P, S375F, K417N, G446S, E484A, G496S, Q498R, Y505H, on the other hand, decreased the binding affinity for ACE2, in agreement with a compensatory effect that moderates the binding strength of the enhancing mutations. [125] However, the reinforced network of hydrogen bonds, involving T500-D355, G502-K353, N487-Y83, as well as R493-D38, and A475-S19, paired with the electrostatic matching between R493-D38 and the loop shift caused by E484A and T478K mutation as suggested by Zhao et al, [126] suggesting an overall increase in the binding energy. These shifts seem to increase the complementarity between ACE2 and Omicron's RBD and could be the reason for the increased binding affinity, as also highlighted by Nie et al [127] The advent of the new VOC highlighted the necessity to follow multiple paths, for a broad-spectrum therapeutic approach, which should not only consider RBD as the target of main interest but should also consider more conserved viral proteins among the variants.…”

Section: Molecular Dynamics Insights On New Sars-cov-2 Variantsmentioning

confidence: 91%

“…[ 124 ] S371L, S373P, S375F, K417N, G446S, E484A, G496S, Q498R, Y505H, on the other hand, decreased the binding affinity for ACE2, in agreement with a compensatory effect that moderates the binding strength of the enhancing mutations. [ 125 ] However, the reinforced network of hydrogen bonds, involving T500‐D355, G502‐K353, N487‐Y83, as well as R493‐D38, and A475‐S19, paired with the electrostatic matching between R493‐D38 and the loop shift caused by E484A and T478K mutation as suggested by Zhao et al., [ 126 ] suggesting an overall increase in the binding energy. These shifts seem to increase the complementarity between ACE2 and Omicron's RBD and could be the reason for the increased binding affinity, as also highlighted by Nie et al.…”

Section: Molecular Dynamics Insights On New Sars‐cov‐2 Variantsmentioning

confidence: 98%

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

et al. 2022

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The SARS‐CoV‐2 virus is responsible for the COVID‐19 pandemic the world experience since 2019. The protein responsible for the first steps of cell invasion, the spike protein, has probably received the most attention in light of its central role during infection. Computational approaches are among the tools employed by the scientific community in the enormous effort to study this new affliction. One of these methods, namely molecular dynamics (MD), has been used to characterize the function of the spike protein at the atomic level and unveil its structural features from a dynamic perspective. In this review, we focus on these main findings, including spike protein flexibility, rare S protein conformational changes, cryptic epitopes, the role of glycans, drug repurposing, and the effect of spike protein variants.

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“…The local influences of these charge-neutral mutations agree with the latest computational studies that are performed on the basis of the AMBER force fields. 21,22 In contrast, the series of charge-altering mutations brings about prominent changes around the central region in the dimer interface, especially at the hotspot 31 and hotspot 353 16 (Figure 2B). Q493R establishes a dominant attraction with E35, contributing −6 kcal/mol to binding, yet the annihilation of the D30−K417 salt bridge as a result of K417N results in a destabilization by around 4 kcal/mol.…”

mentioning

confidence: 99%

Epistatic Variations in the Omicron Receptor Binding Domain Can Enhance Host Recognition: An In Silico Assessment and Prediction

Hou

Gao

Wang

2022

J. Phys. Chem. Lett.

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The hypermutated receptor binding domain (RBD) of the Omicron (B.1.1.529) lineage exhibits a different binding interface with human angiotensinconverting enzyme 2 (ACE2) relative to that of the wild-type Wuhan Hu-1, yet how the altered interaction will affect viral evolution is largely unknown. Here, we used molecular dynamics simulation to characterize the binding features of the Omicron BA.1/hACE2 complex and used free energy perturbation calculations to assess the ongoing and putative variations. The complex reveals a substantial rearrangement of the interfacial hydrogenbond network: R493 of RBD forms a dynamic electrostatic interaction with both E35 and D38 of hACE2, which prohibits the hydrogen bonds of R498−D38 and Y449−D38. Whereas most circulating mutations minimally affect RBD binding to hACE2, the chargealtering mutation R493Q attenuates the affinity by abolishing the electrostatic interaction. However, the potential variants H505Y or N417K/R493Q could restore and gain even greater binding affinities than BA.1 as a result of their optimized interaction network and epistasis effects.

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Origin of the tight binding mode to ACE2 triggered by multi-point mutations in the omicron variant: a dynamic insight

Abstract: The continuous spread of the newly emerged SARS-CoV-2 Omicron variant (B.1.1.529) has become an important reason for the surge in COVID-19 infections. Its numerous mutated residues containing key sites on...

Cited by 11 publications

References 69 publications

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

Epistatic Variations in the Omicron Receptor Binding Domain Can Enhance Host Recognition: An In Silico Assessment and Prediction

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