Investigating the electrostatics underlying activation of the β2 adrenergic receptor.

G-protein coupled receptors (GPCRs) are the largest family of membrane proteins in humans and represent critical targets for drug discovery efforts. Among GPCRs, the β-2 adrenergic receptor (β2AR) has served as a prototypical example of the protein family as well as an important target for pulmonary diseases. As such, much work has been done to investigate this GPCR experimentally and computationally. Many of the interactions that drive activation of β2AR are defined by electrostatics, emphasizing the need for robust simulations with accurate force field models. Only with recent advancements in computing capabilities and refined force fields has it become feasible to simulate this membrane protein on relevant time scales and with sufficiently accurate physical models. Here, we report outcomes of simulations with the Drude polarizable force field to explore the electrostatics underlying β2AR dynamics, marking the first application of explicit electronic polarization in this protein. We found that perturbation of intrinsic dipole moments in key microswitch residues associated with ligand binding is important for subtle conformational changes, resulting in different in conformational sampling compared to a nonpolarizable force field. The results of this study provide a new view of this common drug target with an emphasis on the role of electrostatics.