Structure and Dynamics of the Severe Acute Respiratory Syndrome Coronavirus 2 - Bound Angiotensin-Converting Enzyme 2 : Insight into the Role of a Conserved Disulfide

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus in humans. Coronaviruses are large RNA viruses which contain spike proteins on their surface, giving the appearance of a crown and the name coronavirus. These spike proteins, known as S-proteins, are glycoproteins and type-I transmembrane proteins. The spike contains a receptor-binding domain that functions by binding to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor which is expressed in human lung, heart, kidney, and intestinal cells. For this reason, it is of critical significance to understand the structure of these proteins and the ACE2 host cell receptor they bind to as well as the mechanism of virus entry into the host cell. The binding and entry of the viral protein are impacted by the thiol-disulfide balance on the cell surface. In the present study, the disulfide linkage C480-C488, located close to the binding surface, has been probed by either converting them to thiols or by mutating both cysteines to alanine. The effect of these alterations on structure, key interactions, and protein motions were probed by using long-duration molecular dynamics simulations on a GPU-based high-performance computing cluster. The results of these simulations will be presented.