Differential binding of SARS-CoV-2 Spike protein variants to its cognate receptor hACE2 using molecular modeling based binding analysis.

Anuja Krishnan

doi:10.6026/97320630017337

Abstract

The current emergence of novel coronavirus, SARS-CoV-2 and its ceaseless expansion worldwide has posed a global health emergency that has adversely affected the humans. With the entire world striving to understand the newly emerged virus, differences in morbidity and infection rate of SARS-CoV-2 have been observed across varied geographic areas, which have been ascribed to viral mutation and evolution over time. The homotrimeric Spike (S) glycoprotein on the viral envelope surface is responsible for binding, priming, and initiating infection in the host. Our phylogeny analysis of 1947 sequences of S proteins indicated there is a change in amino acid (aa) from aspartate (Group-A) to glycine (Group-B) at position 614, near the receptor- binding domain (RBD; aa positions 331-524). The two variants are reported to be in circulation, disproportionately across the world, with Group-A dominant in Asia and Group-B in North America. The trimeric, monomeric, and RBD of S protein of both the variant groups (A & B) were modeled using the Swiss-Model server and were docked with the human receptor angiotensin-converting enzyme 2 (hACE2) employing the PatchDock server and visualized in PyMol. Group-A S protein's RBD bound imperceptibly to the two binding clefts of the hACE2 protein, on the other hand, Group-B S protein's RBD perfectly interacted inside the binding clefts of hACE2, with higher number of hydrogen and hydrophobic interactions. This implies that the S protein's amino acid at position 614 near the core RBD influences its interaction with the cognate hACE2 receptor, which may induce its infectivity that should be explored further with molecular and biochemical studies.

Highlights

In December 2019, the city of Wuhan, Hubei province of China, witnessed patients inflicted with severe atypical pneumonia and respiratory illness, reporting the first case of novel coronavirus (CoV-2) infection in December 2019 [1,2]
A total of 176 protein templates were found in the SWISS- MODEL template library (SMTL) based on BLAST, and a total of 676 templates were found by HHblits database searching
Our molecular docking shows that amino acid residues of receptor-binding domain (RBD) S1 domain of S protein of Group-B SARS-CoV-2 strongly interact with amino acid residues of the human AngiotensinConverting Enzyme 2 (hACE2) receptor

Summary

Introduction

In December 2019, the city of Wuhan, Hubei province of China, witnessed patients inflicted with severe atypical pneumonia and respiratory illness, reporting the first case of novel coronavirus (CoV-2) infection in December 2019 [1,2] Since it has grasped and restricted the entire globe, with nearly 85 million cases and more than 1.8 million fatalities as of the first week of January 2021 [3]. We examined 977 S protein sequences deposited across the globe and focused our study on two broad groups, Group-A and B, found primarily in Asia and North America, respectively These two groups differed at a single amino acid (aa) from aspartate (Group-A) to glycine (Group-B) at position 614, which is close to a highly structurally conserved 194 amino acid long receptor-binding domain (RBD), localized at position 331– 524 of the S1 subunit [9]. Using homology modeling (HM) and molecular docking, we tried to analyze differences in the viralreceptor binding, which could plausibly affect variants’ pathogenicity

Methods

Results

Discussion

Conclusion