Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the S688Y Mutation in the NMDA Receptor GluN1 Subunit

Abstract

Encephalopathies are brain dysfunctions that lead to cognitive, sensory, and motor development impairments. Recently, the identification of several mutations within the N-methyl-D-aspartate receptor (NMDAR) have been identified as significant in the etiology of this group of conditions. However, a complete understanding of the underlying molecular mechanism and changes to the receptor due to these mutations has been elusive. We studied the molecular mechanisms by which one of the first mutations within the NMDAR GluN1 ligand binding domain, Ser688Tyr, causes encephalopathies. We performed molecular docking, randomly seeded molecular dynamics simulations, and binding free energy calculations to determine the behavior of the two major co-agonists: glycine and D-serine, in both the wild-type and S688Y receptors. We observed that the Ser688Tyr mutation leads to the instability of both ligands within the ligand binding site due to structural changes associated with the mutation. The binding free energy for both ligands was significantly more unfavorable in the mutated receptor. These results explain previously observed in vitro electrophysiological data and provide detailed aspects of ligand association and its effects on receptor activity. Our study provides valuable insight into the consequences of mutations within the NMDAR GluN1 ligand binding domain.

Role of Computer-Aided Drug Design in Drug Development

“…This study is a typical case of the comprehensive application of drug molecular design methods and helps us gain a deeper understanding of the binding mechanisms between compounds and proteins. In another example, Chen et al [12] performed molecular docking, MD simulations and free energy calculations to study the interactions of two agonists with a wild type and a mutant of the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ionotropic receptor, and elucidated the impact of the mutation on the function of this GluN1 subunit and its associated endogenous ligand affinity. This study is very helpful in providing insight into the design of ligands targeting the mutant of the therapeutic proteins.…”