Molecular dynamics simulations of the SARS-CoV-2 Spike protein and variants of concern: structural evidence for convergent adaptive evolution

Abstract

The Spike protein's structure of the SARS-CoV-2 provides a unique opportunity to consider perturbations at the atomic level. We used the cryo-electron microscopy structure of the open conformation of the Spike protein to assess the impact of the mutations observed in the variants of concern at the molecular level. Molecular dynamics were subsequently performed with both the wt and the mutated forms to compare the flexibility and variation data for each residue of the three-dimensional fluctuations in the region associated with each alpha carbon. Additionally, protein-protein docking was used to investigate the interaction of each mutated profile with the ACE-2 receptor. After the molecular dynamics, the results show that the mutations increased the stability of the trimeric protein, with greater stability observed in the Gamma variant harboring the 10 characteristic mutations. The results of molecular dynamics, as shown by RMSF demonstrated for the residues that comprise the binding domain receptor (RBD), exhibited a reduction in flexibility, which was more pronounced in the Gamma variant. Finally, protein-protein docking experiments revealed an increase in the number of hydrophobic interactions and hydrogen bonds in the Gamma variant against the ACE-2 receptor, as opposed to the other variants. Taken together, these in silico experiments suggest that the evolution of the mutations favored the increased stability of Spike protein while potentially improving its interaction with the ACE-2 receptor, which in turn may indicate putative structural outcomes of the selection of these mutations in the convergent adaptive evolution as it has been observed for SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV2
• molecular dynamics
• variants of concern

Acknowledgments

This article was carried out at the Coordenação-Geral de Laboratórios de Saúde in Brasília, from 2020 to 2021. It was financed by the Fundação de Apoio à FIOCruz. The authors are deeply grateful to Professor Carlos Francisco Sampaio Bonafe (in memoriam) (UNICAMP), Prof. Carlos Prudêncio (Adolfo Lutz Institute) and Prof. Ricardo Zorzetto Nicoliello Vencio for their contributions to the manuscript, analyzes and interpretations of data.

Authors’ contributions

DFLN, VF, and RBK devised the hypothesis. DFLN, RBK conducted the experiments, DFLN, VF, RBK, LD, RJ, ST, VA, AGN, NPL, PMAZ analyzed and interpreted the results, DFLN, VF, RBK, LD, RJ, ST, VA, AGN, NPL, PMAZ, LMOP, CF, EF, BS, ALA, and ACM revised and approved the manuscript.

Disclosure statement

The authors declare no competing interests.

Funding

The author(s) reported there is no funding associated with the work featured in this article.