The impact of receptor-binding domain natural mutations on antibody recognition of SARS-CoV-2

The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including Alpha (B.1.1.7) and Delta (B.1.617.2), some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.

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Design of a companion bioinformatic tool to detect the emergence and geographical distribution of SARS-CoV-2 Spike protein genetic variants

Journal of Translational Medicine ◽

10.1186/s12967-020-02675-4 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Alice Massacci ◽

Eleonora Sperandio ◽

Lorenzo D’Ambrosio ◽

Mariano Maffei ◽

Fabio Palombo ◽

...

Keyword(s):

Receptor Binding ◽

Consensus Sequence ◽

Cell Epitope ◽

Vaccine Design ◽

Binding Domain ◽

Spike Protein ◽

Antibody Activity ◽

Binding Motif ◽

Receptor Binding Domain ◽

The Impact

Abstract Background Tracking the genetic variability of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is a crucial challenge. Mainly to identify target sequences in order to generate robust vaccines and neutralizing monoclonal antibodies, but also to track viral genetic temporal and geographic evolution and to mine for variants associated with reduced or increased disease severity. Several online tools and bioinformatic phylogenetic analyses have been released, but the main interest lies in the Spike protein, which is the pivotal element of current vaccine design, and in the Receptor Binding Domain, that accounts for most of the neutralizing the antibody activity. Methods Here, we present an open-source bioinformatic protocol, and a web portal focused on SARS-CoV-2 single mutations and minimal consensus sequence building as a companion vaccine design tool. Furthermore, we provide immunogenomic analyses to understand the impact of the most frequent RBD variations. Results Results on the whole GISAID sequence dataset at the time of the writing (October 2020) reveals an emerging mutation, S477N, located on the central part of the Spike protein Receptor Binding Domain, the Receptor Binding Motif. Immunogenomic analyses revealed some variation in mutated epitope MHC compatibility, T-cell recognition, and B-cell epitope probability for most frequent human HLAs. Conclusions This work provides a framework able to track down SARS-CoV-2 genomic variability.

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Computational Prediction of the Epitopes of HA1 Protein of Influenza Viruses to its Neutralizing Antibodies

Antibodies ◽

10.3390/antib8010002 ◽

2018 ◽

Vol 8 (1) ◽

pp. 2

Author(s):

Xiaoyan Zeng ◽

Fiona Legge ◽

Chao Huang ◽

Xiao Zhang ◽

Yongjun Jiao ◽

...

Keyword(s):

Influenza Virus ◽

Crystal Structures ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Computational Prediction ◽

Binding Domain ◽

Influenza Viruses ◽

New Method ◽

Receptor Binding Domain ◽

Antibody Recognition

In this work, we have used a new method to predict the epitopes of HA1 protein of influenza virus to several antibodies HC19, CR9114, BH151 and 4F5. While our results reproduced the binding epitopes of H3N2 or H5N1 for the neutralizing antibodies HC19, CR9114, and BH151 as revealed from the available crystal structures, additional epitopes for these antibodies were also suggested. Moreover, the predicted epitopes of H5N1 HA1 for the newly developed antibody 4F5 are located at the receptor binding domain, while previous study identified a region 76-WLLGNP-81 as the epitope. The possibility of antibody recognition of influenza virus via different mechanism by binding to different epitopes of an antigen is also discussed.

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An antibody-escape calculator for mutations to the SARS-CoV-2 receptor-binding domain

10.1101/2021.12.04.471236 ◽

2021 ◽

Author(s):

Allison J Greaney ◽

Tyler N Starr ◽

Jesse D Bloom

Keyword(s):

Receptor Binding ◽

Polyclonal Antibody ◽

Polyclonal Antibodies ◽

Binding Domain ◽

Receptor Binding Domain ◽

Experimental Characterization ◽

Antibody Recognition ◽

Antigenic Properties ◽

Interactive Version

A key goal of SARS-CoV-2 surveillance is to rapidly identify viral variants with mutations that reduce neutralization by polyclonal antibodies elicited by vaccination or infection. Unfortunately, direct experimental characterization of new viral variants lags their sequence-based identification. Here we help address this challenge by aggregating deep mutational scanning data into an "escape calculator" that estimates the antigenic effects of arbitrary combinations of mutations to the virus's spike receptor-binding domain (RBD). The calculator can be used to intuitively visualize how mutations impact polyclonal antibody recognition, and score the expected antigenic effect of combinations of mutations. These scores correlate with neutralization assays performed on SARS-CoV-2 variants, and emphasize the ominous antigenic properties of the recently described Omicron variant. An interactive version of the calculator is at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/escape-calc/, and we provide a Python module for batch processing.

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Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

10.1101/2021.08.30.458225 ◽

2021 ◽

Cited By ~ 1

Author(s):

Nash D. Rochman ◽

Guilhem Faure ◽

Yuri I. Wolf ◽

Peter L. Freddolino ◽

Feng Zhang ◽

...

Keyword(s):

Receptor Binding ◽

Neutralizing Antibodies ◽

Binding Domain ◽

Receptor Binding Domain ◽

Wild Type ◽

Protein Structure Modeling ◽

Escape Mutants ◽

Small Set ◽

Global Concern ◽

The Impact

AbstractAt the time of this writing, August 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Gamma (417T, 484K, 501Y), and Delta variants (452R, 478K). Overall, epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. These results suggest that the repertoire of potential escape mutations for the Delta variant is not substantially different from that of the WT, whereas Gamma poses a moderately greater risk for enhanced vaccine escape. Thus, the modest ensemble of mutations relative to the WT shown to reduce vaccine efficacy might constitute the majority of all possible escape mutations.SignificancePotential emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Gamma and Delta variants. The results indicate that emergence of escape mutants is somewhat less likely for the Delta variant than for the wild type and moderately more likely for the Gamma variant. We conclude that the small set of escape-enhancing mutations already identified for the wild type is likely to include the majority of all possible mutations with this effect, a welcome finding.

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Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

10.1101/2020.12.31.425021 ◽

2021 ◽

Author(s):

Allison J. Greaney ◽

Andrea N. Loes ◽

Katharine H.D. Crawford ◽

Tyler N. Starr ◽

Keara D. Malone ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Binding Motif ◽

Human Antibody ◽

Receptor Binding Domain ◽

Serum Antibodies ◽

Main Target ◽

The Impact ◽

Polyclonal Serum ◽

Comprehensive Mapping

AbstractThe evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

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Landscape of human antibody recognition of the SARS-CoV-2 Receptor Binding Domain

Cell Reports ◽

10.1016/j.celrep.2021.109822 ◽

2021 ◽

pp. 109822

Author(s):

Adam K. Wheatley ◽

Phillip Pymm ◽

Robyn Esterbauer ◽

Melanie H. Dietrich ◽

Wen Shi Lee ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Human Antibody ◽

Receptor Binding Domain ◽

Antibody Recognition

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Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition

Cell Host & Microbe ◽

10.1016/j.chom.2020.11.007 ◽

2020 ◽

Cited By ~ 9

Author(s):

Allison J. Greaney ◽

Tyler N. Starr ◽

Pavlo Gilchuk ◽

Seth J. Zost ◽

Elad Binshtein ◽

...

Keyword(s):

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Antibody Recognition ◽

Complete Mapping

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Interactions of the Receptor Binding Domain of SARS-CoV-2 Variants with hACE2: Insights from Molecular Docking Analysis and Molecular Dynamic Simulation

Biology ◽

10.3390/biology10090880 ◽

2021 ◽

Vol 10 (9) ◽

pp. 880

Author(s):

Ismail Celik ◽

Rohitash Yadav ◽

Zekeriya Duzgun ◽

Sarah Albogami ◽

Ahmed M. El-Shehawi ◽

...

Keyword(s):

Receptor Binding ◽

Experimental Studies ◽

Point Mutations ◽

Protein Docking ◽

Binding Domain ◽

Host Cells ◽

Dynamics Simulation ◽

Receptor Binding Domain ◽

S Protein ◽

The Impact

Since the beginning of the coronavirus 19 (COVID-19) pandemic in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving through the acquisition of genomic mutations, leading to the emergence of multiple variants of concern (VOCs) and variants of interest (VOIs). Currently, four VOCs (Alpha, Beta, Delta, and Gamma) and seven VOIs (Epsilon, Zeta, Eta, Theta, Iota, Kappa, and Lambda) of SARS-CoV-2 have been identified in worldwide circulation. Here, we investigated the interactions of the receptor-binding domain (RBD) of five SARS-CoV-2 variants with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells, to determine the extent of molecular divergence and the impact of mutation, using protein-protein docking and dynamics simulation approaches. Along with the wild-type (WT) SARS-CoV-2, this study included the Brazilian (BR/lineage P.1/Gamma), Indian (IN/lineage B.1.617/Delta), South African (SA/lineage B.1.351/Beta), United Kingdom (UK/lineage B.1.1.7/Alpha), and United States (US/lineage B.1.429/Epsilon) variants. The protein-protein docking and dynamics simulation studies revealed that these point mutations considerably affected the structural behavior of the spike (S) protein compared to the WT, which also affected the binding of RBD with hACE2 at the respective sites. Additional experimental studies are required to determine whether these effects have an influence on drug–S protein binding and its potential therapeutic effect.

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Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

10.1101/2020.09.10.292078 ◽

2020 ◽

Cited By ~ 8

Author(s):

Allison J. Greaney ◽

Tyler N. Starr ◽

Pavlo Gilchuk ◽

Seth J. Zost ◽

Elad Binshtein ◽

...

Keyword(s):

Receptor Binding ◽

Rational Design ◽

Viral Evolution ◽

Neutralizing Antibody ◽

Binding Domain ◽

Escape Mutation ◽

Receptor Binding Domain ◽

Scanning Method ◽

Antibody Recognition ◽

Complete Mapping

AbstractAntibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails–including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.

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