Spike Protein Structural Dynamics of SARS-CoV-2 Coronaviruses Studied Using Molecular Dynamics

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has overwhelmingly impacted the global population, accounting for millions of confirmed infections and deaths over the last year. The virus’s influence on the health and safety of individuals, the economy, and daily life has been disruptive and devastating. While SARS-CoV-2 and SARS-CoV-1, two closely related members of the SARS coronaviruses, have shown the ability to cross the species barrier and infect humans, SARS-CoV-2 has predominantly been the virus responsible for the number of infections presently known. SARS-CoV-2 has also proven to be volatile, as many variants have recently materialized based on amino acid structure mutations. Understanding the differential behavior of the SARS coronaviruses and the many SARS-CoV-2 variants may provide insight into interpreting how the spreading of COVID-19 occurs and could lead to further intuition and discovery. Specifically, studying the structural dynamics of spike proteins that play a crucial role in host cell receptor recognition could expedite the development of vaccines and antivirals that identify sites as potential drug targets. All variants of SARS-CoV-2 recognize the same receptor in humans, yet oftentimes the variants themselves exhibit varying degrees of characteristics such as transmissibility and infectivity. It is implied that the spike proteins, which are the most variable region in the entire genome, may potentially be a source of the different traits these variants present. Specifically, in the lab, we aimed to investigate the activation process of the spike protein and the conformational changes that must occur for the receptor-binding motif (RBM) to be made available for binding to the human receptor (ACE2). We analyzed and targeted the D614G mutation present in many of the SARS-CoV-2 variants and compared it to the differential characteristics present in the wild-type form of the virus. To visualize a detailed account of prefusion spike protein binding to ACE2, we used an extensive set of equilibrium microsecond-level all-atom molecular dynamics simulations. These models are both atomistic and dynamic, allowing us to visualize differences in protein conformation over time at remarkable degrees. The differential behaviors analyzed aided in determining the dynamical changes of the spike proteins and not just their inactive and active states. We determined that the D614G mutation altered sets of interactions throughout the spike protein, potentially resulting in different structural conformations. We also concluded that the D614G variant favored an active state due to increased relative stability, while the original Wild Type variant preferred an inactive state. These results suggest that the D614G mutation may cause variability in the activation mechanisms and stability of virus variants, potentially playing a crucial role in determining the differential characteristics that the viruses possess