Probing the water mediated proton transfer in histidine tautomerization.

• Water assists the histidine tautomerization through hydrogen bond replay. • Water catalyzes the proton transfer process governing the transition between the histidine tautomers. • hiε·(H 2 O) n tautomerism proceeds via a single proton transfer pathway. • Water-assisted histidine tautomerization might be related to the Aβ aggregation hypothesis of Alzheimer's disease. Histidine tautomerism plays a key role in the aggregation of amyloid peptides, which is important for understanding the origin of Alzheimer's disease as well as its diagnosis and treatment. Herein, density functional theory calculations were performed using explicit water molecules and joint implicit/explicit water cluster models to explore the catalytic mechanism and the key role of water assistance effect in the histidine tautomerization reaction. To clarify the proton transfer mechanism involved in histidine tautomerization, three to five water molecules were used to catalyze the proton transfer process governing the transition between the histidine tautomers. Potential energy calculations showed that hiε·(H 2 O) n tautomerism proceeds via a single proton transfer pathway. Systematic analyses of the hydrogen bonds and charge distribution of the key components indicated that tautomerism can be promoted by reducing the number of assistant water molecules or involving the joint implicit/explicit water solvent effect. This study provides theoretical insights into the mechanism of water-assisted histidine isomerization as it relates to the Aβ aggregation hypothesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]