Interactions of the Receptor Binding Domain of SARS-CoV-2 Variants with hACE2: Insights from Molecular Docking Analysis and Molecular Dynamic Simulation

Celik, Ismail; Yadav, Rohitash; Duzgun, Zekeriya; Albogami, Sarah; El-Shehawi, Ahmed M.; , Fatimawali; Idroes, Rinaldi; Tallei, Trina Ekawati; Emran, Talha Bin

SIMPLE SUMMARY: Since the onset of the COVID-19 pandemic in late 2019, SARS-CoV-2 has evolved via genetic changes, resulting in numerous variants of concern (VOCs) and interest (VOIs). Using protein-protein docking and dynamics simulation, we examined the interactions of five SARS-CoV-2 variations’ receptor-binding domains with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells. A comparison of protein-protein docking and dynamics simulations showed that these point mutations significantly altered the structural behavior of the spike (S) protein, affecting RBD binding to hACE2 at the respective sites. Further research is needed to determine whether these changes affect drug–S protein binding and its potential therapeutic impact. ABSTRACT: Since the beginning of the coronavirus 19 (COVID-19) pandemic in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving through the acquisition of genomic mutations, leading to the emergence of multiple variants of concern (VOCs) and variants of interest (VOIs). Currently, four VOCs (Alpha, Beta, Delta, and Gamma) and seven VOIs (Epsilon, Zeta, Eta, Theta, Iota, Kappa, and Lambda) of SARS-CoV-2 have been identified in worldwide circulation. Here, we investigated the interactions of the receptor-binding domain (RBD) of five SARS-CoV-2 variants with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells, to determine the extent of molecular divergence and the impact of mutation, using protein-protein docking and dynamics simulation approaches. Along with the wild-type (WT) SARS-CoV-2, this study included the Brazilian (BR/lineage P.1/Gamma), Indian (IN/lineage B.1.617/Delta), South African (SA/lineage B.1.351/Beta), United Kingdom (UK/lineage B.1.1.7/Alpha), and United States (US/lineage B.1.429/Epsilon) variants. The protein-protein docking and dynamics simulation studies revealed that these point mutations considerably affected the structural behavior of the spike (S) protein compared to the WT, which also affected the binding of RBD with hACE2 at the respective sites. Additional experimental studies are required to determine whether these effects have an influence on drug–S protein binding and its potential therapeutic effect.