Hybrid Quantum and Classical Simulations of the Formate Dehydrogenase Catalyzed Hydride Transfer Reaction on an Accurate Semiempirical Potential Energy Surface

Abstract

Formate dehydrogenase (FDH) catalyzes the oxidation of formic acid to carbon dioxide using nicotinamide adenine dinucleotide (NAD(+)) as a cofactor. In the current work we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the FDH catalyzed hydride transfer. To this end we employ G4MP2 and CBS-QB3 ab initio calculations as well as density functional theory methods. Using these results we develop a specific reaction parameter (SRP) Hamiltonian based on the semiempirical AM1 method. The SRP semiempirical Hamiltonian is subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the FDH catalyzed reaction in Pseudomonas sp. 101 (PseFDH). The classical potential of mean force (PMF) is computed as a function of structural progress coordinates during the course of the hydride transfer reaction: The antisymmetric reactive stretch, the donor-acceptor distance, and an orbital rehybridization coordinate. The quantum PMF is computed using a centroid Feynman path-integral (PI) approach. Subsequently, kinetic isotope effects are computed using a mass-perturbation based PI method. Finally, the antisymmetric stretch vibrational frequency is computed for an azide ion in FDH and in aqueous solution.

Protein Mass Effects on Formate Dehydrogenase

“…39-41 In the reaction catalyzed by FDH, a hydride is transferred from formate ion to the C-4 position of NAD + to generate NADH and CO 2 , as illustrated in Scheme 1. 42 …”

Nuclear quantum effects and kinetic isotope effects in enzyme reactions

“…It is therefore useful to adopt a more pragmatic approach, which involves fine-tuning the PES to the system at hand. This may be achieved for SE methods employing a specific reaction parameter (SRP) approach introduced by Rossi and Truhlar [36], which has been employed in numerous enzymatic reactions [37], including treatments of KIEs [8,[38][39][40][41][42][43]. Another approach is to correct the SE Hamiltonian with a simple valence bond approach, and this has been done very successfully in many KIE applications [5,[44][45][46][47].…”

“…This greatly improved the accuracy of the computed KIE, and has been used extensively since [8,42,43,[88][89][90]92,[100][101][102]. Others have also adopted mass-perturbation techniques for PI KIE in the study of small molecules [103,104].…”

“…A non-exhaustive list of such enzyme studies includes dihydrofolate reductase (DHFR) [41,46,56,90,102,[110][111][112][113][114], alcohol dehydrogenase (ADH) [50,83,115,116], lipoxygenase [55,59,[117][118][119], methylamine dehydrogenase [115,[120][121][122][123][124], thymidylate synthase [125,126], chorismate mutase [127][128][129], several decarboxylases [43,100,101,130], methylmalonyl-CoA mutase [131,132], alanine racemase [39,100,133], formate dehydrogenase [42,134], nitroalkane oxidase [8,108,135], morphinone reductase [116], and glyoxalase [134,136]. In the following we will focus on some examples of work performed in our group, with which ...…”

Ab initio and semi-empirical Molecular Dynamics simulations of chemical reactions in isolated molecules and in clusters

“…Such simulations were reported for the catalysis of hydride transfer reactions by enzymes. 123,124 In these studies, the reaction center is treated by a semi-empirical method, while the rest of the protein is described by empirical force fields. The MD simulations are thus carried out for a QM/MM potential, where the QM part is a semi-empirical model.…”