Molecular Modeling of N-Acetylglucosamine Binding to the I154R Mutant of NAGLU: Pathogenic Insights into Sanfilippo Syndrome Type B

Sanfilippo syndrome type B, also known as mucopolysaccharidosis type IIIB (MPS IIIB), is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetyl-α-D-glucosaminidase (NAGLU) gene, which encodes the enzyme α-N-acetylglucosaminidase. This enzyme is essential for degrading heparan sulfate. The deficiency leads to toxic accumulation within cells. To investigate the impact of NAGLU mutations, mutational data were retrieved from public databases including NCBI, UniProt, and HGMD. A total of 162 variants were evaluated using sequence-based prediction tools to identify deleterious mutations, followed by structure-based in silico analyses to assess changes in protein stability, biophysical properties, and ligand-binding potential. Among the analyzed mutations, the I154R variant was identified as the most deleterious, showing disease-associated characteristics, structural instability, and impaired functional properties. Molecular docking with N-acetylglucosamine (NAG) revealed binding affinities of −4.17 kcal/mol for the native protein and −3.97 kcal/mol for the I154R mutant, suggesting a retained yet slightly reduced binding potential. Molecular dynamics simulations supported these findings, indicating stable trajectories, favorable interaction profiles, and moderate flexibility for both complexes. These results enhance our understanding of NAGLU-related pathogenicity in MPS IIIB, contributing to improved health care strategies and offering a valuable foundation for future therapeutic developments targeting enzyme dysfunction in Sanfilippo syndrome type B.