Molecular Dynamics Simulation Studies to Probe the Impact of Oxidative Stress on the Binding of SARS-CoV-2 Spike Protein to Angiotensin-Converting Enzyme 2

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as well as the human cell surface receptor angiotensin-converting enzyme II (ACE2) contain several cysteine residues. These cysteine residues exist either in the form of disulfide bridges (oxidized) or as thiols (reduced). The thiol-to-disulfide equilibrium is shifted to the right when there are excess reactive oxygen species (ROS) in the body, which is referred to as oxidative stress. It has been shown that certain preexisting conditions, associated with oxidative stress, such as diabetes, obesity, heart conditions, and age can put individuals at a higher risk of contracting COVID-19. Therefore, we hypothesized that the oxidized state of these proteins may have an impact on the binding of the virus protein to the receptor. To test our hypothesis, we used molecular dynamics simulations to study the interacting residues at the binding interface of the complex formed by the receptor-binding domain of SARS-CoV-2 and the peptidase domain of ACE2. Four complexes of ACE2 and SARS-CoV-2 in different redox states were generated by either preserving the disulfides or reducing them to thiols. The preliminary data and findings of this study will be presented.