SARS-CoV-2 beta variant substitutions alter spike glycoprotein receptor binding domain structure and stability

Daniel L Moss,Jay Rappaport

doi:10.1016/j.jbc.2021.101371

Abstract

The emergence of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and the subsequent COVID-19 pandemic have visited a terrible cost on the world in the forms of disease, death, and economic turmoil. The rapid development and deployment of extremely effective vaccines against SARS-CoV-2 have seemingly brought within reach the end of the pandemic. However, the virus has acquired mutations. and emerging variants of concern are more infectious and reduce the efficacy of existing vaccines. Although promising efforts to combat these variants are underway, the evolutionary pressures leading to these variants are poorly understood. To that end, here we have studied the effects on the structure and function of the SARS-CoV-2 spike glycoprotein receptor-binding domain of three amino-acid substitutions found in several variants of concern, including alpha (B.1.1.7), beta (B.1.351), and gamma (P.1). We found that these substitutions alter the receptor-binding domain structure, stability, and ability to bind to angiotensin converting enzyme 2, in such a way as to possibly have opposing and compensatory effects. These findings provide new insights into how these variants of concern may have been selected for infectivity while maintaining the structure and stability of the receptor binding domain.

Highlights

The emergence of SARS-CoV-2 in late 2019 and its subsequent spread around the world has caused the deadliest airborne pandemic in the United States, recently surpassing the 1918 influenza pandemic nearly a century ago[1]
We began our studies on receptor binding domain (RBD) variant of concern substitutions with molecular dynamics to investigate whether single substitutions or all three substitutions the region of residues 468 – 488 in the ff14SB forcefield for the E484K, N501Y, and K417N/E484K/N501Y variants that were not seen for the wild-type and K417N RBD
Quickly form close contacts that are not by molecular dynamics simulation and found observed for the other variants while in that the K417N substitution alone as well as ff14SB these residues are too far apart to Journal Pre-proof the presence of all three substitutions, K417N/E484K/N501Y, within the beta variant RBD may alter the flexibility of a loop region spanning residues 468 – 488 that forms contacts with ACE2

Summary

Introduction

The emergence of SARS-CoV-2 in late 2019 and its subsequent spread around the world has caused the deadliest airborne pandemic in the United States, recently surpassing the 1918 influenza pandemic nearly a century ago[1]. The year 2020 ended with the fastest development of vaccine candidates, starting with the genetic sequence of the virus being reported[2] to human trials of novel mRNA-based vaccines within three of the spike protein within the original Wuhan strain of SARS-CoV-2(4–6). The alpha variant possesses the N501Y substitution within the spike glycoprotein receptor binding domain (RBD) which has been shown to enhance binding to ACE2, the entry receptor for SARS-CoV-2(7–9). The beta and gamma variants possess N501Y as well as substitutions at two other sites within the RBD, E484K, and K417N in beta and K417T in gamma[10] These RBD substitutions present in the spike protein of the B.1.351 and P.1 variants have been shown to reduce the binding and neutralization of mRNA vaccine-induced antibodies as well as potent found within the beta variant would alter RBD human monoclonal antibodies[11]

Methods

Results

Conclusion