The Up state of the SARS-COV-2 Spike homotrimer favors an increased virulence for new variants

The COVID-19 pandemic has spread worldwide. However, as soon as the first vaccines – the only scientifically verified and efficient therapeutic option thus far – were released, mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged, raising doubts about their efficiency. This work aims to explain possible molecular mechanisms, responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor binding domain (RBD) and Angiotensin Converting Enzyme 2 (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state, in which the virus can interact with the cellular receptor ACE2, rather than due to alterations in the complexation RBD-ACE2, since the difference observed in the free energy values was small. Conversely, the South African variant (B.1.351), when compared with the wild type SARS-CoV-2, is much more stable in the opened state with one or two RBDs in the up position than in the closed state with the three RBDs in the down position. Such results contribute to the understanding of the natural history of disease and also indicate possible strategies to develop new therapeutic molecules and to adjust the vaccine doses for a higher production of B cells antibodies.