scholarly journals Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics

2014 ◽  
Vol 16 (14) ◽  
pp. 6398 ◽  
Author(s):  
Yinglong Miao ◽  
Sara E. Nichols ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
G Protein ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
Accelerated Molecular Dynamics ◽  
G Protein Coupled

scholarly journals Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques

2011 ◽  
Vol 7 (10) ◽  
pp. e1002193 ◽  
Author(s):  
Davide Provasi ◽  
Marta Camacho Artacho ◽  
Ana Negri ◽  
Juan Carlos Mobarec ◽  
Marta Filizola
Keyword(s):  
Free Energy ◽  
G Protein ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
Adaptive Biasing ◽  
G Protein Coupled

scholarly journals Imaging G protein–coupled receptors while quantifying their ligand-binding free-energy landscape

2015 ◽  
Vol 12 (9) ◽  
pp. 845-851 ◽  
Author(s):  
David Alsteens ◽  
Moritz Pfreundschuh ◽  
Cheng Zhang ◽  
Patrizia M Spoerri ◽  
Shaun R Coughlin ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
G Protein Coupled

scholarly journals Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243313
Author(s):  
Brandon L. Peters ◽  
Jinxia Deng ◽  
Andrew L. Ferguson
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Intracellular Signaling ◽  
Serotonin Receptor ◽  
Energy Landscape ◽  
Free Energy Calculations ◽  
Free Energy Landscape ◽  
Functional Selectivity ◽  
G Protein Coupled

G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.

scholarly journals Peeking at G-protein-coupled receptors through the molecular dynamics keyhole

2019 ◽  
Vol 11 (6) ◽  
pp. 599-615 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Stefano Moro ◽  
Christopher A Reynolds
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Free-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism

2019 ◽  
Vol 32 (7) ◽  
pp. 297-308 ◽  
Author(s):  
Junichi Higo ◽  
Kota Kasahara ◽  
Mitsuhito Wada ◽  
Bhaskar Dasgupta ◽  
Narutoshi Kamiya ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Binding Pocket ◽  
Free Energy Landscape ◽  
Type B ◽  
Endothelin 1 ◽  
Reaction Coordinates ◽  
Explicit Solvent ◽  
Virtual System ◽  
G Protein Coupled

Abstract The free-energy landscape of interaction between a medium-sized peptide, endothelin 1 (ET1), and its receptor, human endothelin type B receptor (hETB), was computed using multidimensional virtual-system coupled molecular dynamics, which controls the system’s motions by introducing multiple reaction coordinates. The hETB embedded in lipid bilayer was immersed in explicit solvent. All molecules were expressed as all-atom models. The resultant free-energy landscape had five ranges with decreasing ET1–hETB distance: completely dissociative, outside-gate, gate, binding pocket, and genuine-bound ranges. In the completely dissociative range, no ET1–hETB interaction appeared. In the outside-gate range, an ET1–hETB attractive interaction was the fly-casting mechanism. In the gate range, the ET1 orientational variety decreased rapidly. In the binding pocket range, ET1 was in a narrow pathway with a steep free-energy slope. In the genuine-bound range, ET1 was in a stable free-energy basin. A G-protein-coupled receptor (GPCR) might capture its ligand from a distant place.

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