Predictions of the SARS-CoV-2 Omicron Variant (B.1.1.529) Spike Protein Receptor-Binding Domain Structure and Neutralizing Antibody Interactions

Ford, Colby T.; Machado, Denis Jacob; Janies, Daniel

doi:10.1101/2021.12.03.471024

Cited by 28 publications

(26 citation statements)

References 21 publications

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“…Whereas previous variants contained fewer mutations in the S protein and with clear effects on both binding and dynamics (such as N501Y containing variants), Omicron has a larger set of mutations (with more potential for errors in modelling for example) that brings about more mixed results (larger VDS but weaker predicted binding). As the results obtained by Ford et al [21] and those presented here are in agreement, we believe that ignoring insertions and deletions does not substantially impact our results. Considering the fast execution time for our BIS analysis, which makes it possible to analyse large datasets of antibodies, we plan to increase this dataset as more S-antibody structures become available to monitor DS, VDS and BIS for future variants of concern.…”

Section: Discussionsupporting

confidence: 92%

“…The A recent preprint [21] utilized AlphaFold [22] to model the Omicron S protein and the proteinprotein docking software Haddock [23] to predict S-Antibody interactions for four antibodies. It is unclear how small variations in local structure of S as modelled by AlphaFold or of S-antibody complexes as a result of the docking simulation may affect the results.…”

Section: Discussionmentioning

confidence: 99%

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Computational analysis of the effect of SARS-CoV-2 variant Omicron Spike protein mutations on dynamics, ACE2 binding and propensity for immune escape

Teruel

Crown

Bashton

et al. 2021

Preprint

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The recently reported Omicron (B.1.1.529) SARS-CoV-2 variant has a large number of mutations in the Spike (S) protein compared to previous variants. Here we evaluate the potential effect of Omicron S mutations on S protein dynamics and ACE2 binding as contributing factors to infectivity as well as propensity for immune escape. We define a consensus set of mutations from 77 sequences assigned as Omicron in GISAID as of November 25. We create structural models of the Omicron S protein in the open and closed states, as part of a complex with ACE2 and for each of 77 complexes of S bound to different antibodies with known structures. We have previously utilized Dynamical Signatures (DS) and the Vibrational Entropy Score (VDS) to evaluate the propensity of S variants to favour the open state. Here, we introduce the Binding Influence Score (BIS) to evaluate the influence of mutations on binding affinity based on the net gain or loss of interactions within the protein-protein interface. BIS shows excellent correlation with experimental data (Pearson correlation coefficient of 0.87) on individual mutations in the ACE2 interface for the Alpha, Beta, Gamma, Delta and Omicron variants combined. On the one hand, the DS of Omicron highly favours a more rigid open state and a more flexible closed state with the largest VDS of all variants to date, suggesting a large increase in the chances to interact with ACE2. On the other hand, the BIS shows that apart from N501Y, all other mutations in the interface reduce ACE2 binding affinity. VDS and BIS show opposing effects on the overall effectiveness of Omicron mutations to promote binding to ACE2 and therefore initiate infection. To evaluate the propensity for immune escape we calculated the net change of favourable and unfavourable interactions within each S-antibody interface. The net change of interactions shows a positive score (a net increase of favourable interactions and decrease of unfavourable ones) for 41 out of 77 antibodies, a nil score for 15 and a negative score for 21 antibodies. Therefore, in only 28% of S-antibody complexes (21/77) we predict some level of immune escape due to a weakening of the interactions with Omicron S. Considering that most antibody epitopes and the mutations are within the S-ACE2 interface our results suggest that mutations within the RBD of Omicron may give rise to only partial immune escape, which comes at the expense of reduced ACE2 binding affinity. However, this reduced ACE2 affinity appears to have been offset by increasing the occupancy of the open state of the Spike protein.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Computational analysis of the effect of SARS-CoV-2 variant Omicron Spike protein mutations on dynamics, ACE2 binding and propensity for immune escape

Teruel

Crown

Bashton

et al. 2021

Preprint

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“…Pulliam and co-workers performed a retrospective analysis on epidemiological data which indicated that the Omicron variant is associated with an increased ability to evade immunity from previous SARS-CoV-2 infection ( 199 ). Computational predictions have further indicated that the structural changes may decrease antibody interaction but not completely evade neutralizing antibodies ( 200 ).…”

Section: Sars-cov-2 Variantsmentioning

confidence: 99%

SARS-CoV-2 Variants, Vaccines, and Host Immunity

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.

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“…Simulations with the fragment of the original mAbs CR3022 (P00) were also performed for comparison. All these simulations were repeated for RBDs built up with sequences with different mutations of interest present in reported variants (see step 7 in Figure 1 (Kappa/B.1.617.1), (i) G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H (Omicron/B.1.1.529), and (j) Y453F (mink) (Annavajhala et al, 2021, p. 526;Callaway, 2021;Deng et al, 2021;Ford et al, 2021;Khateeb et al, 2021). The input structures with the mutations in the SARS-CoV-2 RBDs were prepared with "UCSF Chimera 1.15" (Pettersen et al, 2004) by the simple replacement of the amino acid followed by a minimization with default parameters and considering the H-bonds (Pettersen et al, 2004).…”

Section: A Fast Constant-ph Coarse-grained (Cg) Approach For Free Energy Calculations On a Large Scalementioning

confidence: 99%

Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants

Neamţu

Mocci

Laaksonen

et al. 2022

Preprint

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A highly efficient and robust multiple scales in silico protocol, consisting of atomistic constant charge Molecular Dynamics (MD), constant-charge coarse-grain (CG) MD and constant-pH CG Monte Carlo (MC), has been used to study the binding affinities, the free energy of complexation of selected antigen-binding fragments of the monoclonal antibody (mAbs) CR3022 (originally derived from SARS-CoV-1 patients almost two decades ago) and 11 SARS-CoV-2 variants including the wild type. CR3022 binds strongly to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein, but chooses a different site rather than the receptor-binding motif (RBM) of RBD, allowing its combined use with other mAbs against new emerging virus variants. Totally 235,000 mAbs structures were generated using the RosettaAntibodyDesign software, resulting in top 10 scored CR3022-RBD complexes with critical mutations and compared to the native one, all having the potential to block virus-host cell interaction. Of these 10 finalists, two candidates were further identified in the CG simulations to be clearly best against all virus variants, and surprisingly, all 10 candidates and the native CR3022 did exhibit a higher affinity for the Omicron variant with its highest number of mutations (15) of them all considered in this study. The multiscale protocol gives us a powerful rational tool to design efficient mAbs. The electrostatic interactions play a crucial role and appear to be controlling the affinity and complex building. Clearly, mAbs carrying a lower net charge show a higher affinity. Structural determinants could be identified in atomistic simulations and their roles are discussed in detail to further hint at a strategy towards designing the best RBD binder. Although the SARS-CoV-2 was specifically targeted in this work, our approach is generally suitable for many diseases and viral and bacterial pathogens, leukemia, cancer, multiple sclerosis, rheumatoid, arthritis, lupus, and more.

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Predictions of the SARS-CoV-2 Omicron Variant (B.1.1.529) Spike Protein Receptor-Binding Domain Structure and Neutralizing Antibody Interactions

Cited by 28 publications

References 21 publications

Computational analysis of the effect of SARS-CoV-2 variant Omicron Spike protein mutations on dynamics, ACE2 binding and propensity for immune escape

Computational analysis of the effect of SARS-CoV-2 variant Omicron Spike protein mutations on dynamics, ACE2 binding and propensity for immune escape

SARS-CoV-2 Variants, Vaccines, and Host Immunity

Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants

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