Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data

and Computer Simulations

Poster Abstracts

33-POS

Board 33

Mapping the Structural Mechanism of the Dopamine 2 Receptor Allosteric Signaling

Pathway with Molecular Dynamics and Evolutionarily Coupled Residues

Dylan Girodat

, Hans-Joachim Wieden.

Alberta RNA Research and Training Institute (ARRTI), University of Lethbridge, Lethbridge,

AB, Canada.

Intramolecular allosteric signaling is required for the proper function of G-protein coupled

receptors (GPCRs). Treatment for a number of neurodegenerative disorders such as Parkinson’s

disease and schizophrenia involve modulation of GPCR activity. As such, novel therapeutics for

these disorders can be rationally designed to target the allosteric signaling pathway of GPCRs

aiming to modulate their activity. However, the mechanism and structural basis of how allosteric

signaling is mediated through GPCRs from the allosteric site to the distal functional site is

unknown. Recently, Sung et al., reported that the identity of distal amino acids in the Dopamine

2 Receptor (D2R) are evolutionarily coupled which can only be explained as residues that are

connected through the D2R allosteric signaling pathway1. We used these coupled residues in

conjunction with Molecular Dynamics (MD) simulations to describe the D2R allosteric signaling

pathway.

Here we present a computational method that analyzes correlations between amino acid

dynamics in MD simulations to describe allosteric signaling. Specifically we use parallel

motions between proximal Cα’s of amino acids in conjunction with network theory to construct

2D maps of allosteric pathways. Using this approach we have described a likely pathway by

which the D2R processes allosteric signals and have gained insight into how residues in the D2R

are evolutionarily coupled contributing to observed functional characteristics of the receptor. Our

work provides a transferable framework to analyse the allosteric regulation of membrane-bound

receptors, enabling the rational design of both receptors with desired behaviors as well as small

molecules and peptides that can modulate their function.

1Sung Y, et al. Intramolecular allosteric communication in dopamine D2 receptor revealed by

evolutionary amino acid covariation. PNAS 2016; 113: 3539-3544