Bioinformatic analysis of the differences in the binding profile of wild type and mutants of the SARS-CoV-2 spike protein variants with the ACE2 receptor

Comput Biol Med. 2021 Oct. 9; 138: 104936. doi: 10.1016 / j.compbiomed.2021.104936. Online before printing.

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). Recently, reports have surfaced of new variants that may increase virulence and virus transmission, as well as reduce the effectiveness of available vaccines. In this study, we computationally analyzed the variants N439K, S477 N and T478K for their ability to bind the angiotensin converting enzyme 2 (ACE2). We used the protein-protein docking approach to investigate whether the three variants have a higher binding affinity for the ACE2 receptor than the wild type. We found that these variants change the hydrogen-bond network and the interaction cluster. Additional salt bridges, hydrogen bonds, and a large number of unbound contacts (i.e. unbound interactions between atoms in the same molecule and those in other molecules) were only observed in the mutated complexes, allowing efficient binding to the ACE2 receptor. In addition, we used a 2.0 μs all-atom simulation approach to identify differences in the structural dynamic properties of the resulting protein complexes. Our results indicated that the mutant complexes exhibited stable dynamics, consistent with the global trend of mutations that yield variants with improved stability and increased affinity. Binding energy calculations based on molecular mechanics / generalized Born surface (MM / GBSA) also showed that electrostatic interactions generally increase the net binding energies. The stability and binding energies of the variants N439K, S477 N and T478K were improved compared to the wild-type ACE2 complex. The net binding energy of the systems was -31.86 kcal / mol for the wild-type ACE2 complex, -67.85 kcal / mol for N439K, -69.82 kcal / mol for S477 N and -69.64 kcal / mol for T478K . The current study provides a basis for research into the improved binding abilities and structural features of SARS-CoV-2 variants in order to develop new therapeutics against the virus.

PMID: 34655895 | DOI: 10.1016 / j.compbiomed.2021.104936