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

Abstract

Aromatic amine dehydrogenase (AADH) and related enzymes are at the heart of debates on the roles of quantum tunneling and protein dynamics in catalysis. The reaction of tryptamine in AADH involves significant quantum tunneling in the rate-limiting proton transfer step, shown by large H/D primary kinetic isotope effects (KIEs), with unusual temperature dependence. We apply correlated ab initio combined quantum mechanics/molecular mechanics (QM/MM) methods, at levels up to local coupled cluster theory (LCCSD(T)/(aug)-cc-pVTZ), to calculate accurate potential energy surfaces for this reaction, which are necessary for quantitative analysis of tunneling contributions and reaction dynamics. Different levels of QM/MM treatment are tested. Multiple pathways are calculated with fully flexible transition state optimization by the climbing-image nudged elastic band method at the density functional QM/MM level. The average LCCSD(T) potential energy barriers to proton transfer are 16.7 and 14.0 kcal/mol for proton transfer to the two carboxylate atoms of the catalytic base, Asp128β. The results show that two similar, but distinct pathways are energetically accessible. 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. These results provide a benchmark for this prototypical enzyme reaction and will be useful for developing empirical models, and analyzing experimental data, to distinguish between different conceptual models of enzyme catalysis.

Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations Support a Concerted Reaction Mechanism for the Zika Virus NS2B/NS3 Serine Protease with Its Substrate

“…98 Note that the barriers here are activation potential energy that cannot be compared directly to a free energy barrier; this would require the calculation of the entropic, tunneling and zero-point energy contributions. 109 The most accurate calculations here, from first principles, are at the LCCSD(T)/(aug)-cc-pVTZ level (barrier height of ~16.3 kcal mol -1 ), which is also in good agreement with experiment (from a rough estimate of these additional contributions) and we use it as a reference for the comparisons. The average barriers from LMP2/(aug)cc-pVTZ and SCS-LMP2/(aug)cc-pVTZ are close (within 1.5 kcal mol -1 ) to the LCCSD(T)/(aug)-cc-pVTZ/ff14SB results.…”

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

“…Figure 5 shows results of embedding different WF methods in B3LYP for the model of the reaction in solution, including Information and Modeling 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 compares more favorably than canonical MP2 to CCSD(T). 9,11,13 There is a significant difference in the energies predicted by the CCSD and CCSD(T) methods (~ 6 kcal/mol),…”

Electronic Structure Benchmark Calculations of CO2 Fixing Elementary Chemical Steps in RuBisCO Using the Projector-Based Embedding Approach

“…26 Here, a computational study of the carboxylase activity of RuBisCO enzyme assesses different ab initio and DFT electronic structure methods for the reaction path proposed by Gready et al 5 The projector-based embedding approach is used: this can eliminate the variability often found when different DFT exchange-correlation functionals (DFT xcfunctional) are selected. [27][28][29][30] This embedding approach has not previously been applied to a metalloenzyme, to our knowledge. This methodology allows us to obtain accurate activation and reaction energies, by describing the most important part of the reactions with a high-level ab initio post-HF electronic structure method, within a DFT treatment of the active-site model.…”