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

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.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Lakkaraju SK,Xue F,Faden AI,MacKerell AD Jr

doi

10.1021/ci400160x

subject

Has Abstract

pub_date

2013-06-24 00:00:00

pages

1337-49

issue

6

eissn

1549-9596

issn

1549-960X

journal_volume

53

pub_type

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