Encephalopathies are brain dysfunctions that lead to cognitive, sensory, and motor development impairments. Recently, the identification of several mutations within theN-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.