The recent emergence of the pathogen
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the
etiological agent for the coronavirus disease 2019 (COVID-19), is
causing a global pandemic that poses enormous challenges to global
public health and economies. SARS-CoV-2 host cell entry is mediated
by the interaction of the viral transmembrane spike glycoprotein (S-protein)
with the angiotensin-converting enzyme 2 gene (ACE2), an essential
counter-regulatory carboxypeptidase of the renin-angiotensin hormone
system that is a critical regulator of blood volume, systemic vascular
resistance, and thus cardiovascular homeostasis. Accordingly, this
work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the
receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular
receptor ACE2 that provides qualitative and quantitative insights
into the main molecular determinants in virus/receptor recognition.
In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498,
T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain
are determined as true hot spots, contributing to shaping and determining
the stability of the relevant protein–protein interface. Overall,
these results could be used to estimate the binding affinity of the
viral protein to different allelic variants of ACE2 receptors discovered
in COVID-19 patients and for the effective structure-based design
and development of neutralizing antibodies, vaccines, and protein/protein
inhibitors against this terrible new coronavirus.