SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation

Nguyen, Hoang Linh; Thai, Nguyen Quoc; Nguyen, Phuong H.; Li, Mai Suan

doi:10.1021/acs.jpcb.2c01048

Cited by 29 publications

(33 citation statements)

References 60 publications

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“…The Omicron BA.2 variant has been reported by both experimental and theoretical studies to have either an enhanced affinity or an affinity similar to that of the Delta variant, causing some debate on the actual affinity of Omicron for ACE2. ,− Our results confirm an affinity close to that of the WT, notwithstanding their very different binding interfaces. As can be seen from Figure , the separation PMFs for Delta and Omicron BA.2 are strikingly similar, which could explain the uncertainty on the reported binding affinity of the two VOCs. ,− …”

Section: Resultssupporting

confidence: 65%

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: Resultssupporting

confidence: 65%

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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“…The higher binding affinity of the omicron variant to the ACE2 compared to the original strain as found in our study is consistent with the results of the MD and docking based computational studies existing in the literature. [ 60 , 61 , 62 , 63 , 64 ] On the other hand, experimental studies report differing results. The surface plasmon resonance (SPR) based experimental studies also support our findings that the binding affinity of the omicron variant to the ACE2 is higher than that of the original strain [ 65 , 66 ] , while a noncompetitive enzyme‐linked immunosorbent assay (ELISA) based experimental study reported a comparable binding affinity for the omicron variant and the original strain.…”

Section: Resultsmentioning

confidence: 99%

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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“…This could suggest that the mutations that cause positive charge tend to be more often associated with stronger binding to the negatively charged surface of ACE2 [21]. Earlier studies have reported that charge increment can enhance ACE2 binding affinity [24,26,27,66–69]. The charge-increasing mutations N439K, N440K, E484A, E484K, E484Q, Q493R and Q498R show near neutral effect (with 0.5 kcal/mol cut-off for neutral, Figure 4a ), but considering the systematic tendency towards weaker binding, this mainly indicates a stronger binding relative to random mutations as can be seen in group comparison in Figure 3 .…”

Section: Resultsmentioning

confidence: 99%

“…Some optimization of ACE2 binding occurred via the D614G mutation which rapidly became dominant in 2020 [23], and ACE2 binding was most likely further improved in subsequent variants alpha, beta, and gamma, via e.g., N501Y and S477N and E484K mutations [24]. The mutation L452R may play a key role in facilitating evolution [25], possibly by modulating changes in electrostatic interactions via positive charges with the predominantly negatively charged ACE2 surface [21,26,27]. There is some disagreement on whether omicron has less [28] or similar [29] binding to ACE2 compared to delta.…”

Section: Introductionmentioning

confidence: 99%

Modelling SARS-CoV-2 spike-protein mutation effects on ACE2 binding

Thakur

Verma

Kepp

et al. 2022

Preprint

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The binding affinity of the SARS-CoV-2 spike (S)-protein ΔΔGbind to the human membrane protein ACE2 is critical for virus function and evolution. Computational structure-based screening of new S-protein mutations for ACE2 binding lends promise to rationalize virus function directly from protein structure and ideally aid early detection of potentially concerning variants. We used a computational protocol based on cryo-electron microscopy structures of the S-protein to estimate the ACE2-binding that gave good trend agreement with experimental ACE2 affinities. We then expanded predictions to all possible S-protein mutations in 21 different S-protein-ACE2 complexes (400,000 ΔΔGbind data points in total), using mutation group comparisons to reduce systematic errors. We show that mutations that have arisen in major variants as a group maintain ACE2 affinity significantly more than random mutations in the total protein, at the interface, and at evolvable sites, with differences between variant mutations being small relative to these effects. Omicron mutations as a group had a modest change in binding affinity compared to mutations in other major variants. The single-mutation effects are consistent with ACE2 binding being optimized and maintained in omicron, despite increased importance of other selection pressures (antigenic drift). As epistasis, glycosylation and in vivo conditions will modulate these effects, computational predictive SARS-CoV-2 evolution remains far from achieved, but the feasibility of large-scale computation is substantially aided by using many structures and comparison of mutation groups rather than single mutation effects, which are very uncertain. Our results demonstrate substantial challenges but indicate ways to improve the quality of computer models for assessing SARS-CoV-2 mutation effects.

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SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation

Cited by 29 publications

References 60 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

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

Modelling SARS-CoV-2 spike-protein mutation effects on ACE2 binding

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