Unbinding of hACE2 and inhibitors from the receptor binding domain of SARS-CoV-2 spike protein

The first direful biomolecular event leading to COVID-19 disease is the SARS-CoV-2 virus surface spike (S) protein-mediated interaction with the human transmembrane protein, angiotensin-converting enzyme 2 (hACE2). Prevention of this interaction presents an attractive alternative to thwart SARS-CoV-2 replications. The development of monoclonal antibodies (mAbs) in the convalescent plasma treatment, nanobody, and designer peptides, which recognizes epitopes that overlap with hACE2 binding sites in the receptor-binding domain (RBD) of S protein (S/RBD) and thereby blocking the infection has been the center stage of therapeutic research. Here we report atomistic and reliable in silico structure-energetic features of the S/RBD interactions with hACE2 and its two inhibitors (convalescent mAb, B38, and an alpaca nanobody, Ty1). The discovered potential of mean forces exhibits free energy basin and barriers along the interaction pathways, providing sufficient molecular insights to design a B38 mutant and a Ty1-based peptide with higher binding capacity. While the mutated B38 forms a 60-fold deeper free energy minimum, the designer peptide (Ty1-based) constitutes 38 amino acids and is found to form a 100-fold deeper free energy minimum in the first binding basin than their wild-type variants in complex with S/RBD. Our strategy may help to design more efficacious biologics towards therapeutic intervention against the current raging pandemic.Communicated by Ramaswamy H. Sarma.