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

Dynamics Simulation ◽

Coarse Grained ◽

Unsaturated Lipids ◽

Bulk Membrane ◽

Enthalpy And Entropy ◽

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.

Structure network analysis to gain insights into GPCR function

Biochemical Society Transactions ◽

10.1042/bst20150283 ◽

2016 ◽

Vol 44 (2) ◽

pp. 613-618 ◽

Cited By ~ 11

Author(s):

Francesca Fanelli ◽

Angelo Felline ◽

Francesco Raimondi ◽

Michele Seeber

Keyword(s):

G Protein ◽

Normal Mode Analysis ◽

Network Models ◽

Md Simulations ◽

Coarse Grained ◽

Mode Analysis ◽

Biomolecular Systems ◽

Retinal Chromophore ◽

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.

An Efficient Molecular Dynamics Simulation Strategy to Investigate the Mechanistic Basis for Biased Agonism at G Protein-Coupled Receptors

Biophysical Journal ◽

10.1016/j.bpj.2017.11.1129 ◽

2018 ◽

Vol 114 (3) ◽

pp. 202a

Author(s):

Derya Meral ◽

Davide Provasi ◽

Marta Filizola

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

G Protein ◽

Dynamics Simulation ◽

Biased Agonism ◽

Simulation Strategy ◽

Mechanistic Basis ◽

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 ◽

Coarse Grained ◽

G Protein Coupled ◽

Coarse Grained Molecular Dynamics ◽

Helix Interactions

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 ◽

Coarse Grained ◽

Novel Computational Methodologies for Structural Modeling of Spacious Ligand Binding Sites of G-Protein-Coupled Receptors: Development and Application to Human Leukotriene B4 Receptor

The Scientific World JOURNAL ◽

10.1100/2012/691579 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Yoko Ishino ◽

Takanori Harada

Keyword(s):

G Protein ◽

Time Scale ◽

Thermal Fluctuations ◽

Leukotriene B4 ◽

Dynamics Simulation ◽

Ligand Docking ◽

Leukotriene B4 Receptor ◽

G Protein Coupled ◽

Gpcr Protein

This paper describes a novel method to predict the activated structures of G-protein-coupled receptors (GPCRs) with high accuracy, while aiming for the use of the predicted 3D structures inin silicovirtual screening in the future. We propose a new method for modeling GPCR thermal fluctuations, where conformation changes of the proteins are modeled by combining fluctuations on multiple time scales. The core idea of the method is that a molecular dynamics simulation is used to calculate average 3D coordinates of all atoms of a GPCR protein against heat fluctuation on the picosecond or nanosecond time scale, and then evolutionary computation including receptor-ligand docking simulations functions to determine the rotation angle of each helix of a GPCR protein as a movement on a longer time scale. The method was validated using human leukotriene B4 receptor BLT1 as a sample GPCR. Our study demonstrated that the proposed method was able to derive the appropriate 3D structure of the active-state GPCR which docks with its agonists.

A complex structure of arrestin-2 bound to a G protein-coupled receptor

10.1101/822957 ◽

2019 ◽

Author(s):

Wanchao Yin ◽

Zhihai Li ◽

Mingliang Jin ◽

Yu-Ling Yin ◽

Parker W. de Waal ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

G Protein ◽

Complex Structure ◽

Transmembrane Helix ◽

Dynamics Simulation ◽

Intracellular Loop ◽

Neurotensin Receptor 1 ◽

AbstractArrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2–NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2–NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.