Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis.

Qifeng Bai,Xiaojun Yao

doi:10.1038/srep21763

Abstract

Metabotropic glutamate receptor 1 (mGlu1), which belongs to class C G protein-coupled receptors (GPCRs), can be coupled with G protein to transfer extracellular signal by dimerization and allosteric regulation. Unraveling the dimer packing and allosteric mechanism can be of great help for understanding specific regulatory mechanism and designing more potential negative allosteric modulator (NAM). Here, we report molecular dynamics simulation studies of the modulation mechanism of FITM on the wild type, T815M and Y805A mutants of mGlu1 through weak interaction analysis and free energy calculation. The weak interaction analysis demonstrates that van der Waals (vdW) and hydrogen bonding play an important role on the dimer packing between six cholesterol molecules and mGlu1 as well as the interaction between allosteric sites T815, Y805 and FITM in wild type, T815M and Y805A mutants of mGlu1. Besides, the results of free energy calculations indicate that secondary binding pocket is mainly formed by the residues Thr748, Cys746, Lys811 and Ser735 except for FITM-bound pocket in crystal structure. Our results can not only reveal the dimer packing and allosteric regulation mechanism, but also can supply useful information for the design of potential NAM of mGlu1.

Highlights

Based on the known crystal structures and MD simulation, MD simulation methods have been successfully used to study the dynamical behavior and elucidate the allosteric regulation mechanism[12,13,14,15,16,17,18]
The negative allosteric modulator FITM locates at the pocket which surrounds by seven helixes of mGlu[1] (Fig. 1A)
To study the structural fluctuations of the entire system, the wild type, T815M and Y805A mutants of mGlu[1] in complex with ions, FITM, cholesterols, lipids and water are built as the initial structure for molecular dynamics simulations (Fig. 1B)

Summary

Introduction

Based on the known crystal structures and MD simulation, MD simulation methods have been successfully used to study the dynamical behavior and elucidate the allosteric regulation mechanism[12,13,14,15,16,17,18]. Due to the specific allosteric sites in the 7TM domain of mGlu[1], negative allosteric modulators (NAM) can be designed based on the crystal structure or known NAM3,20,21. The dynamical dimer mediated by cholesterols and allosteric mechanism of mGlu[1] are still elusive. It is worthwhile to study the detailed dynamical dimer interaction and allosteric mechanism between the homodimers of mGlu[1] and allosteric ligands. Our results supply a detail structural basis for the allosteric and homodimer mechanism of mGlu[1]

Methods

Results

Conclusion