Exploring binding mechanisms of omicron spike protein with dolutegravir and etravirine by molecular dynamics simulation, principal component analysis, and free binding energy calculations.

The COVID-19 pandemic was caused by the SARS-CoV-2 virus, frequent mutations occurred to the wild-type virus resulting in evolved new variants. The WHO classified the new variants as 'Variants of Concern'. SARS-CoV-2 omicron evolved as the dominating variant at the end of 2021. Dolutegravir and etravirine were identified as inhibitors of SARS-CoV-2 entry to host cells in Omicron variants. In this study, combined in silico methods such as molecular docking, molecular dynamics, Principal component analysis, binding-free energy calculations, and Per Residues calculations were applied to investigate the mechanism of the bindings of the two inhibitors. The molecular dynamics results revealed the stability of dolutegravir-spike and etravirine-spike complexes in a similar manner to apo-protein. Dolutegravir and etravirine formed H-bonds and salt bridges with Omicron spike protein. The 2,4-difluoro phenyl moiety of dolutegravir plays an important role in binding the ligand. The binding mode and interactions of the two compounds indicated that Arg403, Tyr449, Tyr453, Arg493, Ser496, Arg498, Thr500, Tyr501, Gln502 and His505 are the key residues. The Principal Component Analyses suggested that no significant conformational changes happened for the two complexes during the simulations. Binding-free energy calculations showed that van der Waals interactions were the most important interactions for ligands' binding. Per-residue free energy decomposition revealed residues Arg493, Arg498, and Tyr501 contributed to the binding of the ligands through H-bonds and salt bridges formation while His505 contributed to H-bonds and Pi-Pi stacking and Phe497 contributed to hydrophobic interactions between ligands and Omicron spike protein.Communicated by Ramaswamy H. Sarma.