Understanding G Protein-Coupled Receptor Allostery via Molecular Dynamics Simulations: Implications for Drug Discovery

Part of the Methods in Molecular Biology book series (MIMB, volume 1762)


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, A2A adenosine receptor (A2AAR). In this chapter, we describe a method for calculating the map of allosteric signal flow in different GPCR conformational 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 words

Allostery G protein-coupled receptor Hotspots Molecular dynamics simulation Network model Structural ensembles 



This work was supported by the Mid-career Researcher Program (NRF-2017R1A2B4010084) funded by the Ministry of Science and ICT (MSIT) through the National Research Foundation of Korea (NRF).


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea

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