Structure, interface stability and hot-spots identification for RBD(SARSCoV- 2):hACE2 complex formation

Abstract

The current COVID-19 pandemic was originally described in China in December 2019 andis caused by a novel coronavirus known as severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2). This virus has spread rapidly throughout the world from itsfirst onset and the World Health Organization (WHO) declared the SARS-CoV-2 globalpandemic on March 11, 2020.In this work, we report a study performed to evaluate details of the structural dynamics,interface stability and molecular interaction between the SARS-CoV-2 receptor bindingdomain (RBD) and its receptor, human angiotensin-converting enzyme 2 (hACE2). Thisstudy provides clarity from a dynamic and energetic point of view.Our dynamic simulation shows that the formation of the RBD:hACE2 complex is primarilydriven by amino acid residues that are principally involved in the formation of ahydrophilic functional cavity, along with a stable and intricate hydrogen bond networkand some salt bridges, with high complementarity between hydrophobic and chargedfunctional groups at the binding interface. The total ΔGbinding remains favourable forRBD:hACE2 complex formation. Noticeably, the binding free energy obtained for thiscomplex is driven by favourable electrostatic interactions rather than by nonpolarinteractions. However, nonpolar interactions should not be neglected in the RBD:hACE2complex formation. Decomposition of binding free energy shows ten hotspot residueslocated on the hACE2 surface. Those residues are located mostly within the structuralelements denoted as helix α1 (Gln24, Thr27, Phe28, Lys31, Tyr41, Gln42), coil regionbetween α2 and 310H1 (Leu79, Met82, Tyr83), and coil region between sheets β4 and β5(Lys353).Favourable contribution to the RBD:hACE2 complex formation arises fromtwelve residues that provide a ?ΔG value of less than 1 kcal/mol. Tyr449, Leu455,Phe456, Ala475, Phe486, Gln493, Gly496, Gln498, Thr500, Asn501, Gly502 and Tyr505were identified as forming the primary interface between the SARS-CoV-2 RBD andhACE2. We believe our results will help to structurally identify and better understand themolecular interactions that occur in these types of complexes and may provide guidancefor the design of new SARS-CoV-2 RBD ligands.