Ab initio QM/MM modelling of Aromatic Amine Dehydrogenase

Aromatic amine dehydrogenase (AADH) and related enzymes are at the heart of debates on the roles of quantum tunnelling and protein dynamics in catalysis (see e.g. Scrutton and Hay, Nature Chemistry 4, 161–168 (2012); Glowacki, Harvey and Mulholland, Nature Chemistry 4, 169-176 (2012)). The reaction of tryptamine in AADH involves significant quantum tunnelling in the rate-limiting proton transfer step, shown e.g. by large H/D primary kinetic isotope effects (KIEs), with unusual temperature dependence (Masgrau et al., Science, 312, 237-241 (2006)).


We apply correlated ab initio combined quantum mechanics/molecular mechanics (QM/MM) methods, at levels up to local coupled cluster theory (the ‘gold standard’ of electronic structure theory), to calculate accurate potential energy surfaces for this reaction. The two carboxylate atoms of the catalytic base, Asp128β, are distinguishable due to their hydrogen bonding environment and proton transfer could occur to either oxygen atom. These two pathways have different barriers, exothermicity and curvature, and should be considered in analyses of the temperature dependence of reaction and KIEs in AADH and other enzymes.


Ab Initio QM/MM Modelling of the Rate-Limiting Proton Transfer Step in the Deamination of Tryptamine by Aromatic Amine Dehydrogenase 

Kara E. Ranaghan, William G. Morris, Laura Masgrau, Kittusamy Senthilkumar, Linus O. Johannissen, Nigel S. Scrutton, Jeremy N. Harvey, Frederick R. Manby, and Adrian J. Mulholland, J. Phys. Chem. B, Just Accepted Manuscript