Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions

Ranaghan, Kara E.; Mulholland, Adrian J.

doi:10.1007/s12539-010-0093-y

Cited by 14 publications

(17 citation statements)

References 147 publications

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“…Although this apparent KIE must not necessarily reflect the true intrinsic KIE, the magnitude is considerably higher than expected for a semiclassical mechanism. [16] One has to bear in mind, however, that the observed KIE results from a combination of several KIEs in different transition states with individual kinetic significances for overall catalysis including several primary (hydrogen abstraction of C8 and subsequent recombination with the peroxyl radical) and a-secondary effects (hydrogen abstraction from C8). Despite a potential combination of KIEs from different transition states, an apparent deuterium KIE of over 30 is usually indicative of hydrogen-tunneling contributions.…”

Section: Deuterium Kinetic Isotope Effect Studies Under Multiple Turnmentioning

confidence: 99%

“…Despite a potential combination of KIEs from different transition states, an apparent deuterium KIE of over 30 is usually indicative of hydrogen-tunneling contributions. [16] Future studies, including a rigorous analysis of the temperature dependence of the apparent KIEs will be carried out to further dissect the molecular mechanism of hydrogen transfer from C8 to the tyrosyl radical. In contrast, dideuteration at C5 has only a marginal influence on the macroscopic kinetic constants of PpoA, as a matter of fact, the effect on V/K is more pronounced than on V. The small deuterium KIE in case of [D 2 ]C5-OA suggests that rearrangement of 8-HPOME at the P450 domain of the enzyme has a little kinetic significance; for example, it is not rate-determining for the overall catalysis.…”

Section: Deuterium Kinetic Isotope Effect Studies Under Multiple Turnmentioning

confidence: 99%

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Influence of Substrate Dideuteration on the Reaction of the Bifunctional Heme Enzyme Psi Factor Producing Oxygenase A (PpoA)

et al. 2011

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PpoA is a bifunctional enzyme that catalyzes the dioxygenation of unsaturated C18 fatty acids. The products of this reaction are termed psi factors and have been shown to play a crucial role in conferring a balance between sexual and asexual spore development as well as production of secondary metabolites in the fungus Aspergillus nidulans. Studies on the reaction mechanism revealed that PpoA uses two different heme domains to catalyze two subsequent reactions. Initially, the fatty acid substrate is dioxygenated at C8, yielding an 8-hydroperoxy fatty acid at the N-terminal domain. This reaction is catalyzed by a peroxidase/dioxygenase-type domain that exhibits many similarities to prostaglandin H2 synthases and involves a stereospecific homolytic hydrogen abstraction from C8 of the substrate. The C terminus harbors a heme thiolate P450 domain in which rearrangement of the 8-hydroperoxide to the final product, a 5,8-dihydroxy fatty acid, takes place. To obtain further information about the intrinsic kinetics and reaction mechanism of PpoA, we synthesized C5-dideutero- and C8-dideutero-oleic acid by a novel protocol that offers a straightforward synthesis without employing the toxic additive hexamethylphosphoramide (HMPA) during CC coupling reactions or mercury salts upon thioketal deprotection. These deuterated fatty acids were then employed for kinetic analysis under multiple-turnover conditions. The results indicate that the hydrogen abstraction at C8 is the rate-determining step of the overall reaction because we observed a KIE (V(H) /V(D) ) of ∼33 at substrate saturation that suggests extensive nuclear tunneling contributions for hydrogen transfer. Deuteration of the substrate at C5, however, had little effect on V(H) /V(D) but resulted in a different product pattern presumably due to an altered lifetime and partitioning of a reaction intermediate.

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Section: Deuterium Kinetic Isotope Effect Studies Under Multiple Turnmentioning

confidence: 99%

Section: Deuterium Kinetic Isotope Effect Studies Under Multiple Turnmentioning

confidence: 99%

Influence of Substrate Dideuteration on the Reaction of the Bifunctional Heme Enzyme Psi Factor Producing Oxygenase A (PpoA)

et al. 2011

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“…The unusually high KIE is likely due to the tunnelling mechanism of the proton transfer. [58,61] A QT study of this process, reported in Ref. [56] …”

Section: Example: a Qt Simulation Of The Proton Transfer In Slo-1mentioning

confidence: 99%

Approximate quantum trajectory dynamics for reactive processes in condensed phase

Garashchuk

Jakowski

Rassolov

2014

Molecular Simulation

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A method of molecular dynamics with quantum corrections, practical for studies of large molecular systems, is reviewed. The approach is based on the Bohmian formulation of the time-dependent Schrödinger equation in which a wavefunction is represented by an ensemble of interdependent trajectories. The quantum effects come from the quantum potential acting on trajectories on par with the usual classical potential. The quantum potential is determined from the evolving nuclear wavefunction, i.e. from the quantum trajectory (QT) ensemble itself. For practical and conceptual reasons the quantum potential and corresponding quantum nuclear effect are computed only for the selected light nuclei. For studies of reactive chemical processes, the classical potential is computed on-the-fly using the density functional tight binding method of electronic structure. A massively parallel implementation, based on the message passing interface allows for efficient simulations of ensembles of thousands of trajectories describing systems of up to 200 atoms. As a biochemical application, the approximate QT approach is used to model the tunnelling-dominated proton transfer in soybean-lipoxygenase-1. A materials science application is represented by a study of the nuclear quantum effect on adsorption of hydrogen and deuterium on a C 37 H 15 molecule, which is a model 'flake' of graphene.Keywords: quantum effect; hybrid dynamics of quantum/classical nuclei; on-the-fly electronic structure; densityfunctional tight-binding method

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“…[10] In addition, for both enzymes, high-resolution crystal structures are available. [53] Both MADH and AADH share an a 2 b 2 hetero-tetrameric structure consisting of two heavy a-subunits and two light bsubunits.T he b-subunits display significant sequence identity and are responsible for the catalytic activity. [52] With high-resolution crystal structures and kinetic datar eadily available, AADH and MADH have been important realistic models for investigating theoretical tunneling processes in enzymes.…”

Section: Introductionmentioning

confidence: 99%

Free‐Energy Landscape and Proton Transfer Pathways in Oxidative Deamination by Methylamine Dehydrogenase

Zelleke

Marx

2016

ChemPhysChem

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The rate-determining step in the reductive half-reaction of the bacterial enzyme methylamine dehydrogenase, which is proton abstraction from the native substrate methylamine, is investigated using accelerated QM/MM molecular dynamics simulations at room temperature. Generation of the multidimensional thermal free-energy landscape without restriction of the degrees of freedom beyond a multidimensional reaction subspace maps two rather similar pathways for the underlying proton transfer to one of two aspartate carboxyl oxygen atoms, termed OD1 and OD2, which hydrogen bond with Thr122 and Trp108, respectively. Despite significant large-amplitude motion perpendicular to the one-dimensional proton transfer coordinate, due to fluctuations of the donor-acceptor distance of about 3 Å, it is found that the one-dimensional proton transfer free-energy profiles are essentially identical to the minimum free-energy pathways on the multidimensional free-energy landscapes for both proton transfer channels. Proton transfer to one of the acceptor oxygen atoms-the OD2 site-is slightly favored in methylamine dehydrogenase by approximately 2 kcal mol , both kinetically and thermodynamically. Mechanistic analyses reveal that the hydrogen bond between Thr122β and OD1 is always present in the transition state independently of the proton transfer channel. Population analysis confirms that the electronic charge gained upon oxidation of the substrate is delocalized within the ring systems of the tryptophan tryptophylquinone cofactor.

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Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions

Cited by 14 publications

References 147 publications

Influence of Substrate Dideuteration on the Reaction of the Bifunctional Heme Enzyme Psi Factor Producing Oxygenase A (PpoA)

Influence of Substrate Dideuteration on the Reaction of the Bifunctional Heme Enzyme Psi Factor Producing Oxygenase A (PpoA)

Approximate quantum trajectory dynamics for reactive processes in condensed phase

Free‐Energy Landscape and Proton Transfer Pathways in Oxidative Deamination by Methylamine Dehydrogenase

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