Dynamics and electrostatics define an allosteric druggable site within the receptor-binding domain of SARS-CoV-2 spike protein

The pathogenesis of the SARS-CoV-2 virus initiates through recognition of the angiotensin-converting enzyme 2 (ACE2) receptor of the host cells by the receptor-binding domain (RBD) located at the spikes of the virus. Here, using molecular dynamics simulations, we have demonstrated the allosteric crosstalk within the RBD in the apo- and the ACE2 receptor-bound states, revealing the contribution of the dynamics-based correlated motions and the electrostatic energy perturbations to this crosstalk. While allostery, based on correlated motions, dominates inherent distal communication in the apo-RBD, the electrostatic energy perturbations determine favorable pairwise crosstalk within the RBD residues upon binding to ACE2. Interestingly, the allosteric path is composed of residues which are evolutionarily conserved within closely related coronaviruses, pointing toward the biological relevance of the communication and its potential as a target for drug development.

Automated summary

The pathogenesis of SARS-CoV-2 virus involves recognition of host cells' ACE2 receptor by the RBD on the virus spikes. Molecular dynamics simulations show allosteric crosstalk within the RBD, influenced by correlated motions and electrostatic energy perturbations. This communication pathway is evolutionarily conserved among related coronaviruses, suggesting potential as a target for drug development.