Role of a Conserved Disulfide on the Interactions Between Severe Acute Respiratory Syndrome Coronavirus 2 and Angiotensin-Converting Enzyme 2

Abstract

Coronaviruses are large, enveloped, positive strand RNA viruses capable of infecting a large array of mammalian and avian species that possess densely glycosylated spike-shaped proteins on their surfaces giving them the appearance of crowns under electron microscope, hence their name. The receptor binding domain (RBD) of the spike protein specifically recognizes and binds to the extracellular peptidase domain of the human angiotensin-converting enzyme 2 (ACE2) with high affinity. There is some evidence to suggest that the entry of viral glycoprotein is affected by the thiol-disulfide balance on the cell surface and disrupting this balance can prevent the virus from being able to infect the host cell. Both the RBD of the spike protein and ACE2 contain several cystine residues, and the existence of several disulfide bridges within them has been established when the species are under oxidative stress. It has also been established that the complete reduction of these disulfide bridges to sulfhydryl groups completely impairs the ability of the RBD to bind to ACE2. However, it is still unknown how each individual disulfide bridge in these proteins impacts the binding. In this study, in a hope to gain an insight into a possible mechanism of disrupting the virus’s life cycle, the disulfide bridge between residues C344 and C361 in ACE2 were probed using molecular dynamics simulations. Results indicated that the removal of the investigated disulfide bridge is insufficient to disable binding between the proteins.