Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations.

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TitleEstimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations.
Publication TypeJournal Article
Year of Publication2013
AuthorsLakkaraju, SKaushik, Xue, F, Faden, AI, Mackerell, AD
JournalJ Chem Inf Model
Volume53
Issue6
Pagination1337-49
Date Published2013 Jun 24
ISSN1549-960X
KeywordsAnimals, Humans, Ligands, Molecular Dynamics Simulation, Protein Conformation, Rats, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate
Abstract

Group 1 metabotropic glutamate receptors (mGluR) are G-protein coupled receptors with a large bilobate extracellular ligand binding region (LBR) that resembles a Venus fly trap. Closing of this LBR in the presence of a ligand is associated with the activation of the receptor. From conformational sampling of the LBR-ligand complexes using all-atom molecular dynamics (MD) simulations, we characterized the conformational minima related to the hinge like motion associated with the LBR closing/opening in the presence of known agonists and antagonists. By applying a harmonic restraint on the LBR, we also determined the conformational forces generated by the different ligands. The change in the location of the minima and the conformational forces were used to quantify the efficacies of the ligands. This analysis shows that efficacies can be estimated from the forces of a single conformation of the receptor, indicating the potential of MD simulations as an efficient and useful technique to quantify efficacies, thereby facilitating the rational design of mGluR agonists and antagonists.

DOI10.1021/ci400160x
Alternate JournalJ Chem Inf Model
PubMed ID23688150
PubMed Central IDPMC3693859
Grant ListR01 GM072558 / GM / NIGMS NIH HHS / United States
GM051501 / GM / NIGMS NIH HHS / United States
R01 GM051501 / GM / NIGMS NIH HHS / United States
R29 GM051501 / GM / NIGMS NIH HHS / United States
GM072558 / GM / NIGMS NIH HHS / United States