Vibrational Energy Landscapes and Energy Flow in GPCRs.

We construct and analyze disconnectivity graphs to provide the first graphical representation of the vibrational energy landscape of a protein, in this study β2AR, a G-protein coupled receptor (GPCR), in active and inactive states. The graphs, which indicate the relative free energy of each residue and the minimum free energy barriers for energy transfer between them, reveal important composition, structural and dynamic properties that mediate the flow of energy. Prolines and glycines, which contribute to GPCR plasticity and function, are identified as bottlenecks to energy transport along the backbone from which alternative pathways for energy transport via nearby noncovalent contacts emerge, seen also in the analysis of first passage time (FPT) distributions presented here. Striking differences between the disconnectivity graphs and FPT distributions for the inactive and active states of β2AR are found where structural and dynamic changes occur upon activation, contributing to allosteric regulation.