Key result
Molecular dynamics simulations revealed that SARS-CoV-2 variants of concern, particularly Omicron and Delta, shifted the receptor binding domain equilibrium toward an open conformation, promoting ACE2 binding.
Why the study?
Previous analyses focused primarily on the direct RBD-ACE2 interaction, ignoring how mutations outside direct contact residues impact the conformational dynamics of the RBD itself.
Molecular dynamics simulations reveal that SARS-CoV-2 variants of concern, particularly Delta and Omicron, alter RBD conformational dynamics to favor an open state, potentially increasing ACE2 binding affinity and aiding antibody escape.
RBD dynamics in variants may aid surveillance; leaves open in vivo or clinical translation from simulations.
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 having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in 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 mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the 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 the 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 being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative “reversed” one, with a significantly changed orientation of the RBM ridge. This alternate conformation could 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 variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.
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Valério et al. (2022) studied SARS-CoV-2. SARS-CoV-2 variants (Alpha, Beta, Delta, Omicron) vs. Wild-type SARS-CoV-2 was evaluated on RBD conformational dynamics (open/closed equilibrium). Molecular dynamics simulations revealed that SARS-CoV-2 variants of concern, particularly Omicron and Delta, shifted the receptor binding domain equilibrium toward an open conformation, promoting ACE2 binding.
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