Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan
Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan
Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-electron microscopy structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down-to-one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.
