Characterization of the dynamic events of GPCRs by automated computational simulations

2013 ◽  
Vol 41 (1) ◽  
pp. 205-212 ◽  
Author(s):  
Hugo Gutiérrez-de-Terán ◽  
Xabier Bello ◽  
David Rodríguez
Keyword(s):  
Structural Information ◽  
Md Simulations ◽  
Dynamic Features ◽  
Computational Simulations ◽  
A2a Adenosine Receptor ◽  
Dynamic Events ◽  
Cxc Chemokine Receptor 4 ◽  
Dynamics Simulations ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

The recent advances in membrane protein crystallography have provided extremely valuable structural information of the superfamily of GPCRs (G-protein-coupled receptors). This has been particularly true for a few receptors whose structure was solved several times under different biochemical conditions. It follows that the mechanisms of receptor conformational equilibrium and related dynamic events can be explored by computational simulations. In the present article, we summarize our recent understanding of several dynamic features of GPCRs, accomplished through the use of MD (molecular dynamics) simulations. Our pipeline for the MD simulations of GPCRs, implemented in the web service http://gpcr.usc.es, is updated in the present paper and illustrated by recent applications. Special emphasis is put on the A2A adenosine receptor, one of the selected cases where crystal structures in several conformations and conditions exist, and on the dimerization process of the CXCR4 (CXC chemokine receptor 4).

scholarly journals Ultraslow water-mediated transmembrane interactions regulate the activation of A2A adenosine receptor

2016 ◽  
Author(s):  
Yoonji Lee ◽  
Songmi Kim ◽  
Sun Choi ◽  
Changbong Hyeon
Keyword(s):  
Adenosine Receptor ◽  
Water Flux ◽  
Active State ◽  
Water Molecules ◽  
A2a Adenosine Receptor ◽  
Functional Roles ◽  
Gpcr Activation ◽  
Tm Domain ◽  
Dynamics Simulations ◽  
G Protein Coupled

Water molecules inside G-protein coupled receptor have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal waters in GPCR activity, we studied A2A adenosine receptor using μsec-molecular dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times slower than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from psec to nsec. Especially, water molecules, exhibiting ultraslow relaxation ( nsec) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow waters in the GPCR activation.

scholarly journals The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors

2019 ◽  
Vol 216 (7) ◽  
pp. 1630-1647 ◽  
Author(s):  
Akiko Nakai ◽  
Jun Fujimoto ◽  
Haruhiko Miyata ◽  
Ralf Stumm ◽  
Masashi Narazaki ◽  
...  
Keyword(s):  
Immune Responses ◽  
Copper Metabolism ◽  
G Protein Coupled Receptors ◽  
Lymphocyte Migration ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Cxc Chemokine Receptor 4 ◽  
Molecular Machinery ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

Lymphocyte migration is mediated by G protein–coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through β-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis. COMMD8, whose stability depended on COMMD3, was recruited to multiple chemoattractant receptors. Deficiency of COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. Using CXC-chemokine receptor 4 (CXCR4) as a model, we demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of β-arrestin–mediated signaling. Thus, the COMMD3/8 complex is a specificity determinant of GRK targeting to GPCRs and represents a point of regulation for immune responses.

scholarly journals Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

2015 ◽  
Vol 48 (4) ◽  
pp. 479-487 ◽  
Author(s):  
Kalli Kappel ◽  
Yinglong Miao ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Partial Agonist ◽  
Md Simulations ◽  
G Protein Coupled Receptor ◽  
Accelerated Molecular Dynamics ◽  
Dynamics Simulations ◽  
G Protein Coupled

AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

scholarly journals β-arrestin mediates communication between plasma membrane and intracellular GPCRs to regulate signaling

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Maxwell S. DeNies ◽  
Alan V. Smrcka ◽  
Santiago Schnell ◽  
Allen P. Liu
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Cxc Chemokine Receptor 4 ◽  
Gpcr Activation ◽  
Cxc Chemokine ◽  
Cationic Channel ◽  
Highly Correlated ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

AbstractIt has become increasingly apparent that G protein-coupled receptor (GPCR) localization is a master regulator of cell signaling. However, the molecular mechanisms involved in this process are not well understood. To date, observations of intracellular GPCR activation can be organized into two categories: a dependence on OCT3 cationic channel-permeable ligands or the necessity of endocytic trafficking. Using CXC chemokine receptor 4 (CXCR4) as a model, we identified a third mechanism of intracellular GPCR signaling. We show that independent of membrane permeable ligands and endocytosis, upon stimulation, plasma membrane and internal pools of CXCR4 are post-translationally modified and collectively regulate EGR1 transcription. We found that β-arrestin-1 (arrestin 2) is necessary to mediate communication between plasma membrane and internal pools of CXCR4. Notably, these observations may explain that while CXCR4 overexpression is highly correlated with cancer metastasis and mortality, plasma membrane localization is not. Together these data support a model where a small initial pool of plasma membrane-localized GPCRs are capable of activating internal receptor-dependent signaling events.

scholarly journals Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

2019 ◽  
Author(s):  
Ye Zou ◽  
John Ewalt ◽  
Ho-Leung Ng
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Protein Activation ◽  
Downstream Signaling ◽  
Dynamics Simulations ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

scholarly journals Comprehensive Modelling of the Self-Folding Cavitand Dynamics

2020 ◽  
Author(s):  
Ricard López-Coll ◽  
Rubén Álvarez-Yebra ◽  
Ferran Feixas ◽  
Agustí Lledó
Keyword(s):  
Rational Design ◽  
Exchange Process ◽  
Md Simulations ◽  
High Energy ◽  
Design Tool ◽  
Dynamic Features ◽  
High Energy Barrier ◽  
Dynamics Simulations ◽  
Good Agreement

<div>The conformational equilibria and guest exchange process of a resorcin[4]arene derived self‐folding cavitand receptor have been modelled in detail by molecular dynamics simulations (MD). A multi‐timescale strategy for exploring the fluxional behavior of this system has been constructed, exploiting conventional MD and accelerated MD (aMD) techniques. The use of aMD allows the reconstruction of the folding/unfolding process of the receptor by sampling high energy barrier processes unattainable by conventional MD simulations. We obtained MD trajectories sampling events occurring at different timescales: 1) rearrangement of the directional hydrogen bond seam stabilizing the receptor, 2) folding/unfolding of the structure transiting partially open intermediates, and c) guest departure from different folding stages. Most remarkably, reweighing of the biased aMD simulations provided kinetic barriers that are in very good agreement with those determined experimentally by 1H NMR. These results constitute the first comprehensive computational characterization of the complex dynamic features of cavitand receptors. Our approach emerges as a valuable rational design tool for synthetic host‐guest systems.</div>

scholarly journals Comprehensive Characterization of the Self-Folding Cavitand Dynamics

2021 ◽  
Author(s):  
Ricard López-Coll ◽  
Rubén Álvarez-Yebra ◽  
Ferran Feixas ◽  
Agustí Lledó
Keyword(s):  
Rational Design ◽  
Exchange Process ◽  
Md Simulations ◽  
High Energy ◽  
Design Tool ◽  
Dynamic Features ◽  
H Nmr ◽  
High Energy Barrier ◽  
Dynamics Simulations

The conformational equilibria and guest exchange process of a resorcin[4]arene derived self-folding cavitand receptor have been characterized in detail by molecular dynamics simulations (MD) and <sup>1</sup>H EXSY experiments. A multi-timescale strategy for exploring the fluxional behavior of this system has been constructed, exploiting conventional MD and accelerated MD (aMD) techniques. The use of aMD allows the reconstruction of the folding/unfolding process of the receptor by sampling high-energy barrier processes unattainable by conventional MD simulations. We obtained MD trajectories sampling events occurring at different timescales from ns to s: 1) rearrangement of the directional hydrogen bond seam stabilizing the receptor, 2) folding/unfolding of the structure transiting partially open intermediates, and c) guest departure from different folding stages. Most remarkably, reweighing of the biased aMD simulations provided kinetic barriers that are in very good agreement with those determined experimentally by <sup>1</sup>H NMR. These results constitute the first comprehensive computational characterization of the complex dynamic features of cavitand receptors. Our approach emerges as a valuable rational design tool for synthetic host-guest systems.<br>

scholarly journals β-arrestin mediates communication between plasma membrane and intracellular GPCRs to regulate signaling

2020 ◽  
Author(s):  
Maxwell S. DeNies ◽  
Alan Smrcka ◽  
Santiago Schnell ◽  
Allen P. Liu
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Cxc Chemokine Receptor 4 ◽  
Gpcr Activation ◽  
Cxc Chemokine ◽  
Cationic Channel ◽  
Highly Correlated ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

AbstractIt has become increasingly apparent that G protein-coupled receptor (GPCR) localization is a master regulator of cell signaling. However, the molecular mechanisms involved in this process are not well understood. To date, observations of intracellular GPCR activation can be organized into two categories: a dependence on OCT3 cationic channel-permeable ligands or the necessity of endocytic trafficking. Using CXC chemokine receptor 4 (CXCR4) as a model, we identified a third mechanism of intracellular GPCR signaling. We show that independent of membrane permeable ligands and endocytosis, upon stimulation, plasma membrane and internal pools of CXCR4 are post-translationally modified and collectively regulate EGR1 transcription. We found that β-arrestin-1 (arrestin 2) is necessary to mediate communication between plasma membrane and internal pools of CXCR4. Notably, these observations may explain that while CXCR4 overexpression is highly correlated with cancer metastasis and mortality, plasma membrane localization is not. Together these data support a model were a small initial pool of plasma membrane-localized GPCRs are capable of activating internal receptor-dependent signaling events.

scholarly journals Comprehensive Modelling of the Self-Folding Cavitand Dynamics

2020 ◽  
Author(s):  
Ricard López-Coll ◽  
Rubén Álvarez-Yebra ◽  
Ferran Feixas ◽  
Agustí Lledó
Keyword(s):  
Rational Design ◽  
Exchange Process ◽  
Md Simulations ◽  
High Energy ◽  
Design Tool ◽  
Dynamic Features ◽  
High Energy Barrier ◽  
Dynamics Simulations ◽  
Good Agreement

<div>The conformational equilibria and guest exchange process of a resorcin[4]arene derived self‐folding cavitand receptor have been modelled in detail by molecular dynamics simulations (MD). A multi‐timescale strategy for exploring the fluxional behavior of this system has been constructed, exploiting conventional MD and accelerated MD (aMD) techniques. The use of aMD allows the reconstruction of the folding/unfolding process of the receptor by sampling high energy barrier processes unattainable by conventional MD simulations. We obtained MD trajectories sampling events occurring at different timescales: 1) rearrangement of the directional hydrogen bond seam stabilizing the receptor, 2) folding/unfolding of the structure transiting partially open intermediates, and c) guest departure from different folding stages. Most remarkably, reweighing of the biased aMD simulations provided kinetic barriers that are in very good agreement with those determined experimentally by 1H NMR. These results constitute the first comprehensive computational characterization of the complex dynamic features of cavitand receptors. Our approach emerges as a valuable rational design tool for synthetic host‐guest systems.</div>

scholarly journals Molecular Conformations of Di-, Tri-, and Tetra-α-(2→8)-Linked Sialic Acid from NMR Spectroscopy and MD Simulations

2019 ◽  
Vol 21 (1) ◽  
pp. 30
Author(s):  
Aysegül Turupcu ◽  
Markus Blaukopf ◽  
Paul Kosma ◽  
Chris Oostenbrink
Keyword(s):  
Sialic Acid ◽  
Nmr Spectroscopy ◽  
Structural Information ◽  
Sampling Technique ◽  
Md Simulations ◽  
Coupling Constants ◽  
Enhanced Sampling ◽  
Molecular Conformations ◽  
J Coupling ◽  
Dynamics Simulations

By using molecular dynamics simulations with an efficient enhanced sampling technique and in combination with nuclear magnetic resonance (NMR) spectroscopy quantitative structural information on α -2,8-linked sialic acids is presented. We used a bottom-up approach to obtain a set of larger ensembles for tetra- and deca-sialic acid from model dimer and trimer systems that are in agreement with the available J-coupling constants and nuclear Overhauser effects. The molecular dynamic (MD) simulations with enhanced sampling are used to validate the force field used in this study for its further use. This empowered us to couple NMR observables in the MD framework via J-coupling and distance restraining simulations to obtain conformations that are supported by experimental data. We used these conformations in thermodynamic integration and one-step perturbation simulations to calculate the free-energy of suggested helical conformations. This study brings most of the available NMR experiments together and supplies information to resolve the conflict on the structures of poly- α -2,8-linked sialic acid.

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