Activation-Induced Reorganization of Energy Transport Networks in the β₂ Adrenergic Receptor

Abstract

We compute energy exchange networks (EENs) through the β2 adrenergic receptor (β2AR), a G-protein coupled receptor (GPCR), in inactive and active states, based on the results of molecular dynamics simulations of this membrane bound protein. We introduce a new definition for the reorganization of EENs upon activation that depends on the relative change in rates of energy transfer across noncovalent contacts throughout the protein. On the basis of the reorganized network that we obtain for β2AR upon activation, we identify a branched pathway between the agonist binding site and the cytoplasmic region, where a G-protein binds to the receptor when activated. The pathway includes all of the motifs containing molecular switches previously identified as contributing to the allosteric transition of β2AR upon agonist binding. EENs and their reorganization upon activation are compared with structure-based contact networks computed for the inactive and active states of β2AR.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…In contrast to multi-pass (integral) membrane proteins, where considerable work has been performed, in particular the GPCR class of membrane proteins e.g., [885][886][887][888][889][890][891][892][893][894][895][896][897][898][899] (for review see references: [31,[900][901][902][903]), that are a very hot topic, peripheral and bitopic (single pass) membrane proteins, which constitute 43-45% of transmembrane proteins [883], are underrepresented in MD simulation studies.…”

A Statistical Journey through the Topological Determinants of the β2 Adrenergic Receptor Dynamics

“…Here, we examine the results of Protein Contact Networks (PCNs) to identify the changes in the network upon activation of the β2-AR, and we compare the results of PCN with the results of Energy Exchange Networks (EENs) [ 39 , 40 , 41 , 42 ] computed for the same GPCR in a recently published computational paper [ 12 ].…”

“…The simulations were set up by taking the coordinates from the protein data bank ID 3P0G [ 19 ] for the active state and 2RH1 [ 20 ] for the inactive state. This paper aims to compare the results of Protein Contact Networks (PCNs) to the results of Energy Transport Networks (EENs) of Reference [ 12 ]. To compare the analysis within the same systems and for consistency in comparison, the same crystal structures used in Reference [ 12 ] were chosen in this study.…”

“…This paper aims to compare the results of Protein Contact Networks (PCNs) to the results of Energy Transport Networks (EENs) of Reference [ 12 ]. To compare the analysis within the same systems and for consistency in comparison, the same crystal structures used in Reference [ 12 ] were chosen in this study. The missing residues of the intracellular loop of the active state were modeled by using Modeller version 9.23 [ 21 ].…”

“…In a previous work [ 12 ], we studied energy transport networks and their reorganization with activation by an agonist, characterizing allosteric switches in charge of the allosteric signal transmission; the identification of the organizing centers of allosteric modulation of the -AR adrenergic receptors plays a relevant role in the drug discovery for these molecular systems.…”