Computational Hot-Spot Analysis of the SARS-CoV-2 Receptor Binding Domain / ACE2 Complex.

Infection and replication of SARS CoV-2 (the virus that causes COVID-19) requires entryto the interior of host cells. In humans, a Protein-Protein Interaction (PPI) between theSARS CoV-2 Receptor-Binding Domain (RBD) and the extracellular peptidase domain ofACE2, on the surface of cells in the lower respiratory tract, is an initial step in the entrypathway. Inhibition of the SARS CoV-2 RBD / ACE2 PPI is currently being evaluated asa target for therapeutic and/or prophylactic intervention. However, relatively little is knownabout the molecular underpinnings of this complex. Employing multiple computationalplatforms, we predicted 'hot-spot' residues in a positive control PPI (PMI / MDM2) and theCoV-2 RBD/ACE2 complex. Computational alanine scanning mutagenesis wasperformed to predict changes in Gibbs' free energy that are associated with mutatingresidues at the positive control (PMI/MDM2) or SARS RBD/ACE2 binding interface toalanine. Additionally, we used the Adaptive Poisson-Boltzmann Solver to calculatemacromolecular electrostatic surfaces at the interface of the positive control PPI andSARS CoV-2 / ACE2 PPI. Finally, a comparative analysis of hot-spot residues for SARSCoVand SARS-CoV-2, in complex with ACE2, is provided. Collectively, this studyilluminates predicted hot-spot residues, and clusters, at the SARS CoV-2 RBD / ACE2binding interface, potentially guiding the development of reagents capable of disruptingthis complex and halting COVID-19.