ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 5 million people and is causing a devastating social and economic impact all over the world. The rise of new variants represents a difficult challenge due to the loss of vaccine and natural immunity, and increased transmissibility. These variants 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). To understand the effect of RBD mutations, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis is limited since it ignores the conformational dynamics of the RBD itself. Observing that some variants 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 molecular dynamics simulations to investigate the structural dynamics of wt RBD, and that of three variants (alpha, beta and delta). 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 significantly impact the open/closed equilibrium, shifting it towards the open conformation by roughly 20%. This shift likely increases ACE2 binding affinity. In the delta variant RBD simulations, the closed conformation was never observed. Instead, the system alternated between the before mentioned open conformation and an alternative 'reversed' one, with a significantly changed orientation of the RBMridge flanking the RBD. These results support the hypothesis that variants impact RBD conformational dynamics in a direction that simultaneously promotes efficient binding to ACE2 and antibody escape.