In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2

Abstract

Abstract The receptor binding motif (RBM) within the S-protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been touted as one of the main targets for vaccine/therapeutic development due to its interaction with the human angiotensin II converting enzyme 2 (hACE2) to facilitate virus entry into the host cell. The mechanism of action is based on the disruption of binding between the RBM and the hACE2 to prevent virus uptake for replication. In this work, we applied in silico approaches to design specific competitive binders for SARS-CoV-2 S-protein receptor binding motif (RBM) by using hACE2 peptidase domain (PD) mutants. Online single point mutation servers were utilised to estimate the effect of PD mutation on the binding affinity with RBM. The PD mutants were then modelled and the binding free energy was calculated. Three PD variants were designed with an increased affinity and interaction with SARS-CoV-2-RBM. It is hope that these designs could serve as the initial work for vaccine/drug development and could eventually interfere the preliminary recognition between SARS-CoV-2 and the host cell.