Mechanism of irreversible conformational locking in the SARS-CoV-2 spike protein induced by transient molecular binding

This study investigates the molecular mechanism of allosteric deactivation of the SARS-CoV-2 spike protein through computational screening and molecular dynamics simulations. We focused on identifying compounds that induce long-lasting conformational changes by targeting non-receptor-binding motif (non-RBM) regions. Our simulations revealed that four small-molecule compounds can stably bind and induce deformations in the receptor-binding motif (RBM), which mask key residues and hinder ACE2 recognition. Most notably, we discovered a unique “hit-and-run” mechanism: one compound, CA5, triggers an irreversible deformation of the RBM after only a transient contact (~1 ns). Crucially, the conformational change persisted long after the drug dissociation. Energetic and structural analysis identifies the cyclopropylamine group (R3 substituent) of CA5 as the key moiety that facilitates its dissociation while locking the protein in an inactive state. This work elucidated a novel biophysical principle for controlling protein conformation through transient interactions, providing a potential strategy for intervening in protein dynamics that is relevant to antiviral therapy.