Exploring the free-energy landscape of GPCR activation

Significance Exploring the action of G-protein–coupled receptors (GPCRs) is a problem of major fundamental and practical importance. Hence, it is crucial to understand the free-energy landscape of the activation of a GPCR. However, at present it is practically impossible to explore this issue by all-atom simulations. The current work uses a coarse-grained (CG) model to explore the nature of the relevant landscape and the resulting GPCR activation. We explore the energetic determinants of the allosteric mechanism of GPCR activation, shedding light on the structure/activity relationship of the system. This advance can serve as a basis for further progress in understanding GPCRs and related systems. Furthermore, it demonstrates the utility of CG approaches in describing and analyzing large and complex biological systems.