N439K Variant in Spike Protein Alter the Infection Efficiency and Antigenicity of SARS-CoV-2 Based on Molecular Dynamics Simulation.

Wenyang Zhou,Anastasia A Anashkina,Yu Guo,Huan Nie,Rui Cheng,Zhaochun Xu,Guangfu Xue,Meng Luo,Liran Juan,Pingping Wang,Xiyun Jin,Chang Xu,Qinghua Jiang

doi:10.3389/fcell.2021.697035

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge with Glu329 of hACE2, which resulted in greater electrostatic complementarity, and created a weak salt bridge with Asp442 of RBD. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. The results show consistent with the previous experimental conclusion and clarify the structural mechanism under affinity changes. Our methods will offer guidance on the assessment of the infection efficiency and antigenicity effect of continuing mutations in SARS-CoV-2.

Highlights

Coronavirus disease 2019 (COVID-19), caused by a single-stranded positive-strand RNA virus named severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), is a major threat to public health worldwide (Wang et al, 2021)
It has been reported that SARS-CoV-2 infects humans through the binding of the homo-trimeric spike (S) glycoprotein to human angiotensin converting enzyme 2, and this infection mechanism for viral entry is used by SARS-CoV
The mutated SARS-CoV-2 receptor binding domain (RBD) was aligned with human angiotensin converting enzyme 2 (hACE2) and monoclonal antibody (mAb) based on the RBDhACE2 and RBD-mAbs structures using PyMOL software

Summary

Introduction

Coronavirus disease 2019 (COVID-19), caused by a single-stranded positive-strand RNA virus named severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), is a major threat to public health worldwide (Wang et al, 2021). It has been reported that SARS-CoV-2 infects humans through the binding of the homo-trimeric spike (S) glycoprotein to human angiotensin converting enzyme 2 (hACE2), and this infection mechanism for viral entry is used by SARS-CoV The surface spike glycoprotein including S1 and S2 subunits is the major antigen of coronaviruses, and S1 binds to host cells whereas S2 mediates viral membrane fusion. The receptor-binding domain (RBD) mediates the binding of the virus to host cells, which is a critical step for viral entry (Hoffmann et al, 2020; Lu et al, 2020; Walls et al, 2020; Zhou et al, 2020). The structural characterization of the pre-fusion S protein provides atomic level information to guide the design and development of antibody (Wrapp et al, 2020; Wu et al, 2020; Wang et al, 2021)

Methods

Results

Conclusion