Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Samantha L Kaye,Mark S.P Sansom,Philip C Biggin

doi:10.1074/jbc.m512728200

Abstract

The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 x 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands. In the case of ligand-bound simulations with both full and partial agonists, we observed that ligands within the binding cleft may undergo distinct conformational changes, without grossly influencing the degree of cleft closure within the ligand-binding domain. In agreement with recently published crystallographic data, we also observe similar changes in backbone torsions corresponding to the hinge region between the two lobes for the partial agonist, D-cycloserine. This observation rationalizes the classification of D-cycloserine as a partial agonist and should provide a basis with which to predict partial agonism in this class of receptor by analyzing the behavior of these torsions with other potential ligands.

Highlights

For the NR1 subunit, unlike the AMPA receptor subunit GluR2, recent crystallographic evidence has suggested that partial agonism is not related to the extent of cleft closure but rather to the efficacy of the ligand to induce a change in the conformation of the hinge region
In the crystal structure of NR1 complexed with the partial agonist D-cycloserine, the conformation of the hinge region was found to be “full agonistlike.”
Our simulations here show that D-cycloserine may be capable of inducing the change in backbone hydrogen bonding of the intersubdomain strands that was found for other partial agonists crystallized (10)

Summary

Introduction

Water in the Binding Pocket—During the Open-Apo simulation, we observed protein motion that results in a conformation that is more closed than the Closed-Apo structure. To characterize the closed conformation in the absence of a ligand more fully, we examined the nature of the interactions of water with the binding pocket.

Results

Conclusion