Abstract

Carbohydrate-active enzymes (CAZymes) encoded by the human gut microbiome are central mediators of dietary glycan metabolism and host–microbe biochemical homeostasis. Among these, β-glucuronidases represent functionally pivotal hydrolases implicated in metabolism, intestinal physiology, and therapeutic modulation. The present study performs an integrative in silico structural and functional interrogation of β-glucuronidases derived from Acidobacterium capsulatum (3VNY), Bacteroides ovatus (6D8K), and Faecalibacterium prausnitzii (6ED2). An integrated computational framework encompassing physicochemical parameters profiling, hierarchical structural prediction, tertiary-structure validation, salt-bridge energetics, functional domain and motif annotation, protein–protein interaction reconstruction, ligand-binding thermodynamics via molecular docking, and residue-resolved non-covalent interaction network mapping using the Protein Contacts Atlas (PCA) was employed. Physicochemical analyses indicated that all enzymes are thermostable, intracellular, and hydrophilic, while secondary-structure organization revealed a functional balance between helix-mediated rigidity and coil-driven flexibility. Structural validation metrics identified 6ED2 as the most conformationally stable architecture, whereas 6D8K displayed enhanced functional complexity, including enriched motif composition, membrane-associated features, and superior ligand-binding affinity. Docking simulations highlighted castanospermine and calcium saccharate as the most favorable interacting ligands across enzyme variants. Importantly, PCA-based interaction analysis revealed distinct ligand-centered atomic contact networks, with immediate contact counts of 57 (3VNY), 32 (6D8K), and 41 (6ED2), providing residue-level insight into stabilization mechanisms and interaction topology beyond conventional docking metrics. Collectively, these findings establish a multidimensional computational framework linking structural stability, functional diversification, ligand recognition, and atomic interaction networks in gut microbial β-glucuronidases, thereby supporting future biochemical validation, microbiome-targeted therapeutics, and biotechnological or cosmeceutical applications.

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