Modelling the catalytic reaction in human aldose reductase

Aldose reductase (ALR2) has received considerable attention due to its poss ible link to long-term diabetic complications. Although crystal structures and kinetic data reveal important aspects of the reaction mechanism, detail s of the catalytic step are still unclear. In this paper a computer simulat ion study is presented that utilizes the hybrid quantum mechanical and mole cular mechanical (QM-MM) potential to elucidate the nature of the hydride a nd proton transfer steps in the reduction of D-glyceraldehyde by ALR2. Seve ral reaction pathways were investigated in two models with either Tyr48 or protonated His110(+) acting as the potential proton donor in the active sit e. Calculations show that the substrate binds to ALR2 through hydrogen bond s in an orientation that facilitates the stereospecific catalytic step in b oth models. It is established that in the case that His110 is. present in t he protonated form in the native complex, it is the energetically favored p roton donor compared with Tyr48 in the active pocket with neutral His110. T he reaction mechanisms in the different models are discussed based on struc tural and energetic considerations. Proteins 1999;87:218-227. (C) 1999 Wile y-Liss, Inc.