Catalytic Reaction Mechanism of Bacterial GH92 α‐1,2‐Mannosidase: A QM/MM Metadynamics Study

Abstract

The catalytic mechanism of a 𝐶𝑎+2‐dependent family 92 α‐ mannosidase, which is abundantly present in human gut flora and malfunctions leading to the lysosomal storage disease a‐ mannosidosis, has been investigated using quantum mechanics/molecular mechanics and metadynamics methods. Computational efforts show that the enzyme follows a conformational itinerary of 0S2/B2,5 → [B2,5]‡ → 1𝑆5, and the 𝐶𝑎+2 ion serves a dual purpose, as it not only distorts the sugar ring but also plays a crucial role in orchestrating the arrangement of catalytic residues. This orchestration, in turn, contributes to the facilitation of 0S2 conformers for the ensuing reaction. This mechanistic insight is well‐aligned with the experimental predictions of the catalytic pathway, and the computed energies are of the same order of magnitude as the experimental estimations. Hence, our results extend the mechanistic understanding of glycosidases.