Structure network analysis to gain insights into GPCR function

G protein coupled receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle. Protein structure network (PSN) analysis is one of the graph theory-based approaches currently used to investigate the structural communication in biomolecular systems. Information on system's dynamics can be provided by atomistic molecular dynamics (MD) simulations or coarse grained elastic network models paired with normal mode analysis (ENM–NMA). The present review article describes the application of PSN analysis to uncover the structural communication in G protein coupled receptors (GPCRs). Strategies to highlight changes in structural communication upon misfolding, dimerization and activation are described. Focus is put on the ENM–NMA-based strategy applied to the crystallographic structures of rhodopsin in its inactive (dark) and signalling active (meta II (MII)) states, highlighting changes in structure network and centrality of the retinal chromophore in differentiating the inactive and active states of the receptor.

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Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms22010187 ◽

2020 ◽

Vol 22 (1) ◽

pp. 187

Author(s):

Pedro Renault ◽

Jesús Giraldo

Keyword(s):

G Protein ◽

Conformational Changes ◽

Drug Targets ◽

Normal Mode Analysis ◽

G Protein Coupled Receptors ◽

Mode Analysis ◽

Allosteric Sites ◽

Basic Hypothesis ◽

Dynamics Simulations ◽

G Protein Coupled

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.

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Influence of oligomerization on the dynamics of G-protein coupled receptors as assessed by normal mode analysis

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.21787 ◽

2008 ◽

Vol 71 (2) ◽

pp. 575-586 ◽

Cited By ~ 26

Author(s):

Masha Y. Niv ◽

Marta Filizola

Keyword(s):

G Protein ◽

Normal Mode ◽

Normal Mode Analysis ◽

G Protein Coupled Receptors ◽

Mode Analysis ◽

G Protein Coupled

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Activation of G-protein coupled receptors is thermodynamically linked to lipid solvation

10.1101/2020.08.20.259077 ◽

2020 ◽

Author(s):

Alison N. Leonard ◽

Edward Lyman

Keyword(s):

G Protein ◽

Chemical Potential ◽

Solvation Shell ◽

G Protein Coupled Receptors ◽

Dynamics Simulation ◽

Coarse Grained ◽

Unsaturated Lipids ◽

Bulk Membrane ◽

Enthalpy And Entropy ◽

G Protein Coupled

AbstractPreferential lipid solvation of the G-protein coupled A2A adenosine receptor (A2AR) is evaluated from 35 μsec of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining statistically robust estimates of the free energy of solvation by different lipids for the receptor in different activation states. Results indicate preference for solvation by unsaturated chains, which favors the active receptor. A model for lipid-dependent GPCR activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The enthalpy and entropy associated with moving saturated vs. unsaturated lipids from bulk to A2AR’s first solvation shell are compared. In the simulated mixture, saturated chains are disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, but this is outweighed by a favorable enthalpic contribution for unsaturated chains to occupy the first solvation shell.

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An Ensemble-Based Protocol for the Computational Prediction of Helix–Helix Interactions in G Protein-Coupled Receptors using Coarse-Grained Molecular Dynamics

Journal of Chemical Theory and Computation ◽

10.1021/acs.jctc.6b01246 ◽

2017 ◽

Vol 13 (5) ◽

pp. 2254-2270 ◽

Cited By ~ 19

Author(s):

Nojood A. Altwaijry ◽

Michael Baron ◽

David W. Wright ◽

Peter V. Coveney ◽

Andrea Townsend-Nicholson

Keyword(s):

Molecular Dynamics ◽

G Protein ◽

Computational Prediction ◽

G Protein Coupled Receptors ◽

Coarse Grained ◽

G Protein Coupled ◽

Coarse Grained Molecular Dynamics ◽

Helix Interactions

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G-Protein coupled receptors: answers from simulations

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.13.106 ◽

2017 ◽

Vol 13 ◽

pp. 1071-1078 ◽

Cited By ~ 9

Author(s):

Timothy Clark

Keyword(s):

Molecular Dynamics ◽

Drug Design ◽

G Protein ◽

Experimental Situation ◽

Md Simulations ◽

G Protein Coupled Receptors ◽

Computer Aided Drug Design ◽

Computer Aided ◽

Soft And Hardware ◽

G Protein Coupled

Molecular-dynamics (MD) simulations are playing an increasingly important role in research into the modes of action of G-protein coupled receptors (GPCRs). In this field, MD simulations are unusually important as, because of the difficult experimental situation, they often offer the only opportunity to determine structural and mechanistic features in atomistic detail. Modern combinations of soft- and hardware have made MD simulations a powerful tool in GPCR research. This is important because GPCRs are targeted by approximately half of the drugs on the market, so that computer-aided drug design plays a major role in GPCR research.

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Ligand Pose Predictions for Human G Protein-Coupled Receptors: Insights from the Amber-Based Hybrid Molecular Mechanics/Coarse-Grained Approach

Journal of Chemical Information and Modeling ◽

10.1021/acs.jcim.0c00661 ◽

2020 ◽

Vol 60 (10) ◽

pp. 5103-5116 ◽

Cited By ~ 1

Author(s):

Jakob Schneider ◽

Ksenia Korshunova ◽

Zeineb Si Chaib ◽

Alejandro Giorgetti ◽

Mercedes Alfonso-Prieto ◽

...

Keyword(s):

Molecular Mechanics ◽

G Protein ◽

G Protein Coupled Receptors ◽

Coarse Grained ◽

G Protein Coupled

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Coarse-Grained Protein Dynamics Studies Using Elastic Network Models

International Journal of Molecular Sciences ◽

10.3390/ijms19123899 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3899 ◽

Cited By ~ 5

Author(s):

Yuichi Togashi ◽

Holger Flechsig

Keyword(s):

Normal Mode Analysis ◽

Protein Structures ◽

Computational Cost ◽

Network Models ◽

Coarse Grained ◽

Mode Analysis ◽

Nonlinear Phenomena ◽

Reference Structure ◽

Elastic Network ◽

Elastic Network Models

Elastic networks have been used as simple models of proteins to study their slow structural dynamics. They consist of point-like particles connected by linear Hookean springs and hence are convenient for linear normal mode analysis around a given reference structure. Furthermore, dynamic simulations using these models can provide new insights. As the computational cost associated with these models is considerably lower compared to that of all-atom models, they are also convenient for comparative studies between multiple protein structures. In this review, we introduce examples of coarse-grained molecular dynamics studies using elastic network models and their derivatives, focusing on the nonlinear phenomena, and discuss their applicability to large-scale macromolecular assemblies.

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