Molecular dynamics trajectories for "SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessiblity"

Dataset of molecular dynamics trajectories obtained for "SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessiblity"

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is causing a devastating social and economic impact all over the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, and increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes, via its receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2). In an attempt to understand the effect of RBD mutations in the VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some VOCs mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (alpha, beta, delta, and omicron). Our results show that, in solution, wt RBD presents two distinct conformations: an “open” conformation where it is free to bind ACE2; and a “closed” conformation, where the RBM ridge blocks the binding surface. The alpha and beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the delta and omicron variants showed extreme results, with the closed conformation either barely observed or not observed at all. The delta variant also differed from the other variants substantially, alternating between the open conformation and an alternative “reversed” one, with a significantly changed orientation of the RBM ridge. This alternate conformation could potentially provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the omicron and delta variant, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of delta, antibody escape.