SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: A Computational Model of Epitope Loss in Variants of Concern.

Alice Triveri,Silvia Pavoni,Andrea Rasola,Elisabetta Moroni,Fabrizio Cinquini,Filippo Marchetti,Francesco Frigerio,Filippo Doria,Stefano A Serapian,Giorgio Colombo

doi:10.1021/acs.jcim.1c00857

Abstract

The SARS-CoV-2 spike (S) protein is exposed on the viral surface and is the first point of contact between the virus and the host. For these reasons it represents the prime target for Covid-19 vaccines. In recent months, variants of this protein have started to emerge. Their ability to reduce or evade recognition by S-targeting antibodies poses a threat to immunological treatments and raises concerns for their consequences on vaccine efficacy. To develop a model able to predict the potential impact of S-protein mutations on antibody binding sites, we performed unbiased multi-microsecond molecular dynamics of several glycosylated S-protein variants and applied a straightforward structure-dynamics-energy based strategy to predict potential changes in immunogenic regions on each variant. We recover known epitopes on the reference D614G sequence. By comparing our results, obtained on isolated S-proteins in solution, to recently published data on antibody binding and reactivity in new S variants, we directly show that modifications in the S-protein consistently translate into the loss of potentially immunoreactive regions. Our findings can thus be qualitatively reconnected to the experimentally characterized decreased ability of some of the Abs elicited against the dominant S-sequence to recognize variants. While based on the study of SARS-CoV-2 spike variants, our computational epitope-prediction strategy is portable and could be applied to study immunoreactivity in mutants of proteins of interest whose structures have been characterized, helping the development/selection of vaccines and antibodies able to control emerging variants.

Highlights

Protein sequences evolve as a result of selective pressure to optimize function, create improved phenotypes, and introduce new advantageous traits
We first run 4 independent 1 μs long all-atom molecular dynamics (MD) simulations of each variant of the full-length fully glycosylated S protein in solution (Figure 1)
We analyzed full-length models of 7 trimeric glycosylated SARS-CoV-2 S protein variants, derived from the prefusion conformation of the Cryo-EM structure 6VSB,[11] in which the receptor binding domain of chain A (RBD-A) is in an “up” conformation, exposed to interaction with host cell receptors and potential targeting by Abs

Summary

Introduction

Protein sequences evolve as a result of selective pressure to optimize function, create improved phenotypes, and introduce new advantageous traits. The spread of the virus to more than 200 million people worldwide, combined with the pressure determined by the reactions of immunocompetent populations, led to the emergence of “variants of concern” In this context, attention has been focused on the SARS-CoV-2 spike protein (S protein), the large, heavily glycosylated class I trimeric fusion protein which mediates host cell recognition, binding and entry. Three notable examples of such evolved S proteins, which correspond to major circulating variants, are B.1.1.7 (the so-called UK or α variant), 501Y.V2/ B.1.351 (the South African or β variant), and B.1.1.28 (P.1, the Brazilian or γ variant) All such sequences contain various mutations due to nonsynonymous nucleotide changes in the receptor-binding domain (RBD), including E484K, N501Y, and/or K417N.10. All such sequences contain various mutations due to nonsynonymous nucleotide changes in the receptor-binding domain (RBD), including E484K, N501Y, and/or K417N.10 In B.1.1.7 and B.1.351, deletions are present in the N-terminal domains (NTD) (Figure 1)

Methods

Results

Conclusion