Computational Drug Discovery and Design

Chapter 23

Understanding G Protein-Coupled Receptor Allostery

via Molecular Dynamics Simulations: Implications

for Drug Discovery

Shaherin Basith, Yoonji Lee, and Sun Choi

Abstract

Unraveling the mystery of protein allostery has been one of the greatest challenges in both structural and
computational biology. However, recent advances in computational methods, particularly molecular
dynamics (MD) simulations, have led to its utility as a powerful and popular tool for the study of protein
allostery. By capturing the motions of a protein’s constituent atoms, simulations can enable the discovery of
allosteric hot spots and the determination of the mechanistic basis for allostery. These structural and
dynamic studies can provide a foundation for a wide range of applications, including rational drug design
and protein engineering. In our laboratory, the use of MD simulations and network analysis assisted in the
elucidation of the allosteric hotspots and intracellular signal transduction of G protein-coupled receptors
(GPCRs), primarily on one of the adenosine receptor subtypes, A2Aadenosine receptor (A2AAR). In this
chapter, we describe a method for calculating the map of allosteric signal flow in different GPCR confor-
mational states and illustrate how these concepts have been utilized in understanding the mechanism of
GPCR allostery. These structural studies will provide valuable insights into the allosteric and orthosteric
modulations that would be of great help to design novel drugs targeting GPCRs in pathological states.

Key wordsAllostery, G protein-coupled receptor, Hotspots, Molecular dynamics simulation, Net-

work model, Structural ensembles

1 Introduction

For more than five decades, researchers have been involved in

understanding the mechanism for signal transmission across long

distances in biologically active macromolecules, which forms the

basis for allostery. Protein allostery is a biophysical phenomenon

which explains the ability of interactions occurring at one site to

modulate interactions at a spatially distinct binding site in a recip-

rocal manner [1]. Thus, studying the mechanistic interplay

between active and allosteric sites is crucial to better understand

Mohini Gore and Umesh B. Jagtap (eds.),Computational Drug Discovery and Design, Methods in Molecular Biology, vol. 1762,
https://doi.org/10.1007/978-1-4939-7756-7_23,©Springer Science+Business Media, LLC, part of Springer Nature 2018

Author contributed equally with all other contributors. Shaherin Basith and Yoonji Lee

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