Site Density Functional Theory and Structural Bioinformatics Analysis of the SARS-CoV Spike Protein and hACE2 Complex.

Nitesh Kumawat,Marat Valiev,Sergey E Kruchinin,Koji Tsuda,Gennady N Chuev,Amit Chakraborty,Marina V Fedotova,Adnan Sljoka,Soumen Bera,Andrejs Tucs

doi:10.3390/molecules27030799

Abstract

The entry of the SARS-CoV-2, a causative agent of COVID-19, into human host cells is mediated by the SARS-CoV-2 spike (S) glycoprotein, which critically depends on the formation of complexes involving the spike protein receptor-binding domain (RBD) and the human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2). Using classical site density functional theory (SDFT) and structural bioinformatics methods, we investigate binding and conformational properties of these complexes and study the overlooked role of water-mediated interactions. Analysis of the three-dimensional reference interaction site model (3DRISM) of SDFT indicates that water mediated interactions in the form of additional water bridges strongly increases the binding between SARS-CoV-2 spike protein and hACE2 compared to SARS-CoV-1-hACE2 complex. By analyzing structures of SARS-CoV-2 and SARS-CoV-1, we find that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) has expanded in size, indicating large conformational change relative to SARS-CoV-1 S protein. Protomer with the up-conformational form of RBD, which binds with hACE2, exhibits stronger intermolecular interactions at the RBD-ACE2 interface, with differential distributions and the inclusion of specific H-bonds in the CoV-2 complex. Further interface analysis has shown that interfacial water promotes and stabilizes the formation of CoV-2/hACE2 complex. This interaction causes a significant structural rigidification of the spike protein, favoring proteolytic processing of the S protein for the fusion of the viral and cellular membrane. Moreover, conformational dynamics simulations of RBD motions in SARS-CoV-2 and SARS-CoV-1 point to the role in modification of the RBD dynamics and their impact on infectivity.

Highlights

The coronavirus pandemic COVID-19, caused by Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2), continues to pose a serious threat across continents
Recent work has revealed that the S-protein in the open state with at least one receptor-binding domain (RBD) in the “up” conformation, corresponds to the receptor accessible conformation that can bind to human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2)
In a recently reported structure of SARS-CoV-2, it was observed that hACE2 can only bind when the RBD adapts an open upconformational state [65]

Summary

Introduction

The coronavirus pandemic COVID-19, caused by Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2), continues to pose a serious threat across continents. To better understand virus transmissibility, a large number of molecular studies have focused on the viral entry processes that are mediated by the spike glycoprotein (S protein), which is responsible for the receptor recognition and membrane fusion [2,3]. The S protein protomer is made of two subunits S1 and S2 The former unit, which comprises the receptor-binding domain (RBD), binds to the peptidase domain of hACE2 and contributes to stabilization of the prefusion conformational state. The SARS-CoV uses ectodomain trimer to mediate this viral entry [4,5]. Both SARS-CoV-1 and SARS-CoV-2 recognize hACE2 through its RBD, which is positioned within the flexible S1 unit of S-protein protomer

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