posted on 2021-03-18, 14:37authored byErik Laurini, Domenico Marson, Suzana Aulic, Alice Fermeglia, Sabrina Pricl
The coronavirus disease-2019 (COVID-19)
pandemic, caused by the
pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
started in China during late 2019 and swiftly spread worldwide. Since
COVID-19 emergence, many therapeutic regimens have been relentlessly
explored, and although two vaccines have just received emergency use
authorization by different governmental agencies, antiviral therapeutics
based neutralizing antibodies and small-drug inhibitors can still
be vital viable options to prevent and treat SARS-CoV-2 infections.
The viral spike glycoprotein (S-protein) is the key molecular player
that promotes human host cellular invasion via recognition of and
binding to the angiotensin-converting enzyme 2 gene (ACE2). In this
work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain
(S-RBDCoV‑2) residues that contribute to the receptor/viral
protein binding interface. Specifically, each wild-type protein–protein
interface residue was replaced by a hydrophobic (isoleucine), polar
(serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine),
and bulky (tryptophan) residue, respectively, in order to study the
different effects exerted by nature, shape, and dimensions of the
mutant amino acids on the structure and strength of the resulting
binding interface. The computational results were next validated a posteriori against the corresponding experimental data,
yielding an overall agreement of 92%. Interestingly, a non-negligible
number of mis-sense variations were predicted to enhance ACE2/S-RBDCoV‑2 binding, including the variants Q24T, T27D/K/W,
D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W,
F456K/W, Q493K, N501T, and Y505W on S-RBDCoV‑2,
respectively.