Résumé
A replica-exchange protocol remarkably enhances the sampling of the activation dynamics of the neurotensin receptor type 1, a G protein-coupled receptor (GPCR) and important drug target. Our work highlights the dynamic communication between conformational changes of the agonist and the G protein-binding site, via contraction-oscillation of the orthosteric pocket. It also gives insights into the mechanism by which certain mutations diminish or stimulate activation. The replica-exchange protocol effectively enhances barrier crossing where standard brute-force molecular dynamics simulations fail. It is readily applicable to other GPCRs and represents a promising approach for virtual ligand screening, using the typical features of receptor activation as a benchmark.