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Bifidobacteriumis a genus of Gram-positivebacteria, which is important in the absorption of nourishment fromthe human milk oligosaccharides (HMO). We present here the detailedsimulation of the enzymatic hydrolysis of 2′-fucosyllactosecatalyzed by 1,2-α-l-fucosidase from Bifidobacterium bifidumusing the combined quantummechanical and molecular mechanical approach. Molecular dynamics simulationsand free energy profiles support that the overall reaction is a stepwisemechanism. The first step is the proton transfer from N423 to D766,and the second step involves the hydrolysis reaction via the inversionmechanism catalyzed by the amide group of N423. Assisted by D766,N423 serves as the general base to activate the water molecule toattack the anomeric carbon center. E566 is the general acid to facilitatethe cleavage of glycosidic bond between l-fucose and galactoseunits. The intrinsic resonance structure for the side chain amidegroup of the asparagine residue is shown to be the origin to the catalyticactivity, which is also confirmed by the mutagenesis simulation ofN423G. [ABSTRACT FROM AUTHOR]