Mutational Analysis of SARS-CoV-2 Variants of Concern Reveals Key Tradeoffs Between Receptor Affinity and Antibody Escape

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2022 May 31

PMID 35639784

Authors

Emily K Makowski

John S Schardt

Matthew D Smith

Peter M Tessier

Affiliations

Soon will be listed here.

Abstract

SARS-CoV-2 variants with enhanced transmissibility represent a serious threat to global health. Here we report machine learning models that can predict the impact of receptor-binding domain (RBD) mutations on receptor (ACE2) affinity, which is linked to infectivity, and escape from human serum antibodies, which is linked to viral neutralization. Importantly, the models predict many of the known impacts of RBD mutations in current and former Variants of Concern on receptor affinity and antibody escape as well as novel sets of mutations that strongly modulate both properties. Moreover, these models reveal key opposing impacts of RBD mutations on transmissibility, as many sets of RBD mutations predicted to increase antibody escape are also predicted to reduce receptor affinity and vice versa. These models, when used in concert, capture the complex impacts of SARS-CoV-2 mutations on properties linked to transmissibility and are expected to improve the development of next-generation vaccines and biotherapeutics.

Citing Articles

Deep mutational learning for the selection of therapeutic antibodies resistant to the evolution of Omicron variants of SARS-CoV-2.

Frei L, Gao B, Han J, Taft J, Irvine E, Weber C Nat Biomed Eng. 2025; .

PMID: 40044817 DOI: 10.1038/s41551-025-01353-4.

Variation and evolution analysis of SARS-CoV-2 using self-game sequence optimization.

Liu Z, Shen Y, Jiang Y, Zhu H, Hu H, Kang Y Front Microbiol. 2024; 15:1485748.

PMID: 39588108 PMC: 11586374. DOI: 10.3389/fmicb.2024.1485748.

Genetic diversity and genomic epidemiology of SARS-CoV-2 during the first 3 years of the pandemic in Morocco: comprehensive sequence analysis, including the unique lineage B.1.528 in Morocco.

Djorwe S, Malki A, Nzoyikorera N, Nyandwi J, Zebsoubo S, Bellamine K Access Microbiol. 2024; 6(10).

PMID: 39376591 PMC: 11457919. DOI: 10.1099/acmi.0.000853.v4.

SARS-CoV-2 Genomic Epidemiology Dashboards: A Review of Functionality and Technological Frameworks for the Public Health Response.

Sitharam N, Tegally H, Silva D, Baxter C, de Oliveira T, Xavier J Genes (Basel). 2024; 15(7).

PMID: 39062655 PMC: 11275337. DOI: 10.3390/genes15070876.

Co-Mutations and Possible Variation Tendency of the Spike RBD and Membrane Protein in SARS-CoV-2 by Machine Learning.

Ye Q, Wang H, Xu F, Zhang S, Zhang S, Yang Z Int J Mol Sci. 2024; 25(9).

PMID: 38731879 PMC: 11083383. DOI: 10.3390/ijms25094662.

References

Starr T, Thornton J . Epistasis in protein evolution. Protein Sci. 2016; 25(7):1204-18. PMC: 4918427. DOI: 10.1002/pro.2897. View

Harvey W, Carabelli A, Jackson B, Gupta R, Thomson E, Harrison E . SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021; 19(7):409-424. PMC: 8167834. DOI: 10.1038/s41579-021-00573-0. View

Midelfort K, Wittrup K . Context-dependent mutations predominate in an engineered high-affinity single chain antibody fragment. Protein Sci. 2006; 15(2):324-34. PMC: 2242459. DOI: 10.1110/ps.051842406. View

Andreano E, Piccini G, Licastro D, Casalino L, Johnson N, Paciello I . SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma. Proc Natl Acad Sci U S A. 2021; 118(36). PMC: 8433494. DOI: 10.1073/pnas.2103154118. View

Kustin T, Harel N, Finkel U, Perchik S, Harari S, Tahor M . Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nat Med. 2021; 27(8):1379-1384. PMC: 8363499. DOI: 10.1038/s41591-021-01413-7. View

Mannar D, Saville J, Zhu X, Srivastava S, Berezuk A, Tuttle K . SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein-ACE2 complex. Science. 2022; 375(6582):760-764. DOI: 10.1126/science.abn7760. View

Starr T, Greaney A, Hilton S, Ellis D, Crawford K, Dingens A . Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. Cell. 2020; 182(5):1295-1310.e20. PMC: 7418704. DOI: 10.1016/j.cell.2020.08.012. View

Greaney A, Loes A, Gentles L, Crawford K, Starr T, Malone K . Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Sci Transl Med. 2021; 13(600). PMC: 8369496. DOI: 10.1126/scitranslmed.abi9915. View

Rani P, Imran M, Lakshmi J, Jolly B, Jain A, Surekha A . Symptomatic reinfection of SARS-CoV-2 with spike protein variant N440K associated with immune escape. J Med Virol. 2021; 93(7):4163-4165. PMC: 8250729. DOI: 10.1002/jmv.26997. View

10.

Bayarri-Olmos R, Rosbjerg A, Johnsen L, Helgstrand C, Bak-Thomsen T, Garred P . The SARS-CoV-2 Y453F mink variant displays a pronounced increase in ACE-2 affinity but does not challenge antibody neutralization. J Biol Chem. 2021; 296:100536. PMC: 7948531. DOI: 10.1016/j.jbc.2021.100536. View

11.

Greaney A, Starr T, Barnes C, Weisblum Y, Schmidt F, Caskey M . Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies. Nat Commun. 2021; 12(1):4196. PMC: 8263750. DOI: 10.1038/s41467-021-24435-8. View

12.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215-220. DOI: 10.1038/s41586-020-2180-5. View

13.

Ozono S, Zhang Y, Ode H, Sano K, Tan T, Imai K . SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nat Commun. 2021; 12(1):848. PMC: 7870668. DOI: 10.1038/s41467-021-21118-2. View

14.

Weisblum Y, Schmidt F, Zhang F, DaSilva J, Poston D, Lorenzi J . Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. 2020; 9. PMC: 7723407. DOI: 10.7554/eLife.61312. View

15.

van Dorp L, Acman M, Richard D, Shaw L, Ford C, Ormond L . Emergence of genomic diversity and recurrent mutations in SARS-CoV-2. Infect Genet Evol. 2020; 83:104351. PMC: 7199730. DOI: 10.1016/j.meegid.2020.104351. View

16.

Garcia-Beltran W, Lam E, St Denis K, Nitido A, Garcia Z, Hauser B . Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell. 2021; 184(9):2372-2383.e9. PMC: 7953441. DOI: 10.1016/j.cell.2021.03.013. View

17.

Ali F, Kasry A, Amin M . The new SARS-CoV-2 strain shows a stronger binding affinity to ACE2 due to N501Y mutant. Med Drug Discov. 2021; 10:100086. PMC: 7923861. DOI: 10.1016/j.medidd.2021.100086. View

18.

Ou J, Zhou Z, Dai R, Zhang J, Zhao S, Wu X . V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity. J Virol. 2021; 95(16):e0061721. PMC: 8373230. DOI: 10.1128/JVI.00617-21. View

19.

Laurini E, Marson D, Aulic S, Fermeglia A, Pricl S . Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence. ACS Nano. 2021; 15(4):6929-6948. PMC: 8009103. DOI: 10.1021/acsnano.0c10833. View

20.

Greaney A, Loes A, Crawford K, Starr T, Malone K, Chu H . Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe. 2021; 29(3):463-476.e6. PMC: 7869748. DOI: 10.1016/j.chom.2021.02.003. View