Integrative Evolutionary and Structural Analysis of GBA1 Provides Insights Into Mutation‐Specific Effects Associated With Parkinson's Disease

GBA1 encodes lysosomal acid β-glucosidase (glucocerebrosidase [GCase]), a key lysosomal enzyme and one of the most important genetic factors in Parkinson's disease (PD). Yet how different GBA1 variants influence PD-related molecular pathology remains incompletely understood. Here, we integrated phylogenetic, comparative sequence, structural, docking, and molecular dynamics analyses to identify evolutionarily constrained features of GBA1 that may influence its interaction with α-synuclein (SNCA) and thereby contribute to PD pathogenesis. Phylogenetic reconstruction indicated that GBA1 originated early in bilaterian evolution and was maintained as a single-copy gene in the sampled taxa, consistent with strong functional constraint. Sequence-based analyses across sarcopterygian lineages further supported pervasive purifying selection, especially within the TIM barrel catalytic domain. Comparative structural analyses highlighted a conformationally sensitive segment spanning Residues 379-389, which includes catalytic and neighboring residues and showed recurrent involvement in both mammalian evolution and PD-associated mutant proteins. Docking and molecular dynamics simulations of wild-type and mutant GBA1-SNCA complexes indicated that PD-associated substitutions can remodel hydrogen-bond networks and influence the conformational landscape of the GBA1-SNCA complex in a mutation-specific manner. Although no statistically significant differences in global structural or energetic properties were detected, individual variants exhibited distinct patterns of conformational deviation, flexibility, and interaction dynamics relative to wild type. In particular, Residues 387-389 emerged as part of a structurally responsive region linked to altered GBA1-SNCA association. Together, these findings highlight candidate structural determinants for future experimental studies of GBA1-associated neurodegeneration.