Probing the Allosteric Inhibition Mechanism of a Spike Protein Using Molecular Dynamics Simulations and Active Compound Identifications

The receptor recognition of the novel
coronavirus SARS-CoV-2 relies
on the “down-to-up” conformational change in the receptor-binding
domain (RBD) of the spike (S) protein. Therefore, understanding the
process of this change at the molecular level facilitates the design
of therapeutic agents. With the help of coarse-grained molecular dynamic
simulations, we provide evidence showing that the conformational dynamics
of the S protein are globally cooperative. Importantly, an allosteric
path was discovered that correlates the motion of the RBD with the
motion of the junction between the subdomain 1 (SD1) and the subdomain
2 (SD2) of the S protein. Building on this finding, we designed non-RBD
binding modulators to inhibit SARS-CoV-2 by prohibiting the conformational
change of the S protein. Their inhibition effect and function stages
at inhibiting SARS-CoV-2 were evaluated experimentally. In summary,
our studies establish a molecular basis for future therapeutic agent
design through allosteric effects.