Structural Dynamics of Prefusion Spike Protein of SARS-CoV-2 and its Variants: Insights from Molecular Dynamics*

The rapidly evolving COVID-19 pandemic has claimed many lives and crippled economies around the world. SARS-COV-2, the virus behind the pandemic, uses spike proteins to infect human cells by binding to ACE2 receptors on various host cells. Multiple mutants have emerged, among which there have been thriving variants with increased transmissibility and capacity for immune evasions. Static structures of wild-type spike proteins are insufficient to understand the evolving process of activation and infection. Here we have used microsecond-level molecular dynamics (MD) simulations to study the active and inactive states of the spike proteins on the wild-type, Alpha, Beta, Gamma, Epsilon, and Delta variants, as well as an engineered spike protein associated with the Moderna vaccine. Our simulations reveal specific mutations, which are responsible for the differential dynamic behavior of variants. These particular mutations could potentially be associated with higher transmissibility and immune evasion potential of the viruses by altering the activation path and active structures. This study provides insight into the dynamic behavior of the spike protein of different SARS-CoV-2 variants, which is key to identifying targets for the development of novel vaccines and therapeutic agents.