Serine 477 plays a crucial role in the interaction of the SARS-CoV-2 spike protein with the human receptor ACE2

Amit Singh,Karl Gruber,Katharina Köchl,Christian C Gruber,Georg Steinkellner

doi:10.1038/s41598-021-83761-5

Amit Singh, Karl Gruber + Show 3 more

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https://doi.org/10.1038/s41598-021-83761-5

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Abstract

Since the worldwide outbreak of the infectious disease COVID-19, several studies have been published to understand the structural mechanism of the novel coronavirus SARS-CoV-2. During the infection process, the SARS-CoV-2 spike (S) protein plays a crucial role in the receptor recognition and cell membrane fusion process by interacting with the human angiotensin-converting enzyme 2 (hACE2) receptor. However, new variants of these spike proteins emerge as the virus passes through the disease reservoir. This poses a major challenge for designing a potent antigen for an effective immune response against the spike protein. Through a normal mode analysis (NMA) we identified the highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 up to residue 485. Structurally, the position S477 shows the highest flexibility among them. At the same time, S477 is hitherto the most frequently exchanged amino acid residue in the RBDs of SARS-CoV-2 mutants. Therefore, using MD simulations, we have investigated the role of S477 and its two frequent mutations (S477G and S477N) at the RBD during the binding to hACE2. We found that the amino acid exchanges S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor.

Highlights

Since the worldwide outbreak of the infectious disease COVID-19, several studies have been published to understand the structural mechanism of the novel coronavirus SARS-CoV-2
We found that the amino acid exchanges S477G and S477N strengthen the binding of the SARS-COV-2 spike with the human angiotensin-converting enzyme 2 (hACE2) receptor
While preparing potential targets of the SARS-CoV-2 proteome for our recently published large-scale virtual screening[6,7] aiming to identify potential binders and inhibitors, we analysed the diversity of the SARS-CoV-2 genome landscape: Till 30th August 2020, among 73,042 reported SARS-CoV-2 spike sequences on GISAID we have found that a total of 185 amino acid substitutions are reported on the 223 residues long receptor binding domain (RBD) and 68 exchanges are reported in the 72 residues long RBM (Fig. 1a)[8]

Summary

Introduction

Since the worldwide outbreak of the infectious disease COVID-19, several studies have been published to understand the structural mechanism of the novel coronavirus SARS-CoV-2. Through a normal mode analysis (NMA) we identified the highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 up to residue 485. We found that the amino acid exchanges S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor. SARS-CoV-2 is responsible for around 1.8 million deaths as of December 2020 This novel virus is a member of structurally “crowned” viruses, first appreciated and defined as coronavirus in the 1960’s when Tyrrell and Bynoe discovered the first human coronaviruses (HCoVs)[1]. The SARS-CoV-2 spike receptor binding domain (RBD) is known to interact with the human angiotensin-converting enzyme 2 (hACE2) r eceptor[2,3]. NMA has been used previously to resolve the domain motions and dynamical correlation among protein residues[24,25]

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