The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
Hisham Dokainish, Suyong Re, Takaharu Mori, Chigusa Kobayashi, Jaewoon Jung, Yuji Sugita
Abstract
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 RBD A and RBD C and the interaction with glycan at N343 B support RBD A motions from Down to one-Up. Reduced interactions between RBD A and RBD B in one-Up induce RBD B 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.