tetano
Editor, Senior Moderator
Elife
. 2022 Mar 24;11:e75720.
doi: 10.7554/eLife.75720. Online ahead of print.
The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
Hisham M Dokainish[SUP] 1 [/SUP], Suyong Re[SUP] 2 [/SUP], Takaharu Mori[SUP] 3 [/SUP], Chigusa Kobayashi[SUP] 4 [/SUP], Jaewoon Jung[SUP] 4 [/SUP], Yuji Sugita[SUP] 1 [/SUP]
Affiliations
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[SUB]A[/SUB] and RBD[SUB]C[/SUB] and the interaction with glycan at N343[SUB]B[/SUB] support RBD[SUB]A[/SUB] motions from Down to one-Up. Reduced interactions between RBD[SUB]A[/SUB] and RBD[SUB]B[/SUB] in one-Up induce RBD[SUB]B[/SUB] motions toward two-Up. The simulations overall agree with cryo-EM 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: biochemistry; chemical biology; human; molecular biophysics; structural biology.
. 2022 Mar 24;11:e75720.
doi: 10.7554/eLife.75720. Online ahead of print.
The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
Hisham M Dokainish[SUP] 1 [/SUP], Suyong Re[SUP] 2 [/SUP], Takaharu Mori[SUP] 3 [/SUP], Chigusa Kobayashi[SUP] 4 [/SUP], Jaewoon Jung[SUP] 4 [/SUP], Yuji Sugita[SUP] 1 [/SUP]
Affiliations
- PMID: 35323112
- DOI: 10.7554/eLife.75720
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[SUB]A[/SUB] and RBD[SUB]C[/SUB] and the interaction with glycan at N343[SUB]B[/SUB] support RBD[SUB]A[/SUB] motions from Down to one-Up. Reduced interactions between RBD[SUB]A[/SUB] and RBD[SUB]B[/SUB] in one-Up induce RBD[SUB]B[/SUB] motions toward two-Up. The simulations overall agree with cryo-EM 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: biochemistry; chemical biology; human; molecular biophysics; structural biology.