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.
Keywords: SARS-CoV-2; biochemistry; chemical biology; conformational transition; cryptic pockets; enhanced sampling; human; molecular biophysics; spike protein; structural biology.
© 2022, Dokainish et al.