Agonist and Antagonist Interactions in Beta Adrenergic Receptors

Abstract

G-protein coupled receptors (GPCRs) are a large family of integral membrane proteins involved in signal transduction pathways, making them appealing drug targets for a wide spectrum of diseases. The recently solved X-ray structures of beta1 (B1AR) and beta2 (B2AR) adrenergic receptors bound to inverse agonists/antagonists open up a large field of potential investigations to understand the binding modes and mechanisms of activation of GPCRs.To investigate their structural and dynamic properties under pseudo in vivo conditions, we performed extensive molecular dynamics simulations (in an explicit membrane) of adrenergic receptors in complex with partial inverse agonists and agonists as well as in their apoform. To this end, we applied MD-based enhanced sampling techniques (steered MD, metadynamics, …) to describe ligand binding and to elucidate the process of ligand entrance and release.In this contribution, we rationalize the differences in binding mode between B1AR and B2AR for both agonists and antagonists (focusing on a limited set of key residues surrounding the binding pocket that are different between B1AR and B2AR). We also discuss main structural changes upon agonist/antagonist binding also in comparison with the most thoroughly studied GPCR, rhodopsin.