ChemInform Abstract: BOND ORDER METHODS FOR CALCULATING ISOTOPE EFFECTS IN ORGANIC REACTIONS

Sims, L. B.; Lewis, David E.

doi:10.1002/chin.198505355

Cited by 7 publications

(13 citation statements)

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“…We used the Bigeleisen−Mayer equation to calculate isotope effects for the YADH-catalyzed oxidation of benzyl alcohol by NAD + (eq 4). ,, This equation requires only knowledge of vibrational frequencies and their isotopic dependencies for reactants and transition states in order to calculate isotope effects. Since isotope effects are local phenomena, only the parts of the molecule containing the isotopically labeled atom(s) need be included.…”

Section: Methodsmentioning

confidence: 99%

“…Transition state internal coordinates are shown in Figure . Most geometric parameters and diagonal force constants in the transition state were assigned as a weighted average of reactant and product parameters which can be represented numerically as where A denotes reactant ( A r ), product ( A p ), or transition state ( A ts ) force constants or geometric parameters and X represents the progress of the transition state toward product. , Primary hydrogen bond lengths were assigned using the Pauling equation assuming that bond order is conserved around the reacting hydrogen. Linear bending coordinates (23 and 24 in Figure ) were assigned using the method given by Huskey…”

Section: Methodsmentioning

confidence: 99%

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Computational Study of Tunneling and Coupled Motion in Alcohol Dehydrogenase-Catalyzed Reactions: Implication for Measured Hydrogen and Carbon Isotope Effects

Rucker

Klinman

1999

J. Am. Chem. Soc.

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The relationship between the two hydrogen isotope effects, k H /k T and k D /k T , can provide a probe for the role of tunneling and coupled motion in enzyme-catalyzed reactions. 1,2 Using vibrational analysis and the Bigeleisen-Mayer equation, we have developed a simple computational model to explain the unusual exponential relationships that have been experimentally observed in the yeast alcohol dehydrogenase (YADH) 3 -catalyzed oxidation of benzyl alcohol. 2 The experimental results are fitted by a model that has both substantial hydrogen tunneling and coupling between the reaction coordinate and a large number of vibrational modes. We show that the secondary k D /k T isotope effect is expected to be the most sensitive parameter to changes in reaction coordinate properties. A high degree of coupled motion leads to an unexpected suppression of the semiclassical secondary isotope effects, resulting in secondary isotope effects which are primarily manifestations of tunneling. This has implications for the use of secondary hydrogen isotope effects as probes of transition state position. During the course of these computational studies, primary carbon isotope effects were shown to undergo a consistent increase in magnitude upon substitution of the transferring protium with deuterium. We suggest that this effect can be explained using simple semiclassical principles and will apply to a broad range of reactions. Inference of reaction mechanism from the observation of a change in a heavy-atom isotope effects upon substrate deuteration should be interpreted with caution when the position of heavy atom and hydrogen isotope substitution are the same.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Computational Study of Tunneling and Coupled Motion in Alcohol Dehydrogenase-Catalyzed Reactions: Implication for Measured Hydrogen and Carbon Isotope Effects

Rucker

Klinman

1999

J. Am. Chem. Soc.

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“…Kinetic isotope theory and kinetic isotope effects (KIEs) were first developed for isotope fractionation and later used to deduce chemical mechanisms in organic chemistry and transition-state features for solution-based chemical reactions (24–27). The application of isotope effects to enzymatic reactions became more practical with the publication of books summarizing the theory and methods for approaching problems with isotope effects in enzymology (28, 29).…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Schramm

2011

Annu. Rev. Biochem.

199

235

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Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits (a) the design of transition-state analogs as powerful enzymatic inhibitors, (b) exploration of protein features linked to transition-state structure, (c) analysis of ensemble atomic motions involved in achieving the transition state, (d) transition-state lifetimes, and (e) separation of ground-state (Michaelis complexes) from transition-state effects. Transition-state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein’s dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states.

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“…The atoms omitted in the construction of the cutoff model for transition state modeling were the 2, and 5 hydroxylic hydrogen atoms and the 3 hydroxyl group of the ribose ring along with N1, C2, and the exocylic amino group of the purine ring. Force constants for the various vibrational modes were derived from reported values (Sims et al, 1977;Sims and Lewis, 1984). The starting point for the ground-state of adenosine was its crystal structure (Lai and Marsh, 1972).…”

Section: Transition-state Modelingmentioning

confidence: 99%

“…Due to the limitation on the maximum number of atoms available in the BEBOVIB-IV program, a cutoff model containing only relevant atoms was used (Sims and Lewis, 1984). The atoms omitted in the construction of the cutoff model for transition state modeling were the 2, and 5 hydroxylic hydrogen atoms and the 3 hydroxyl group of the ribose ring along with N1, C2, and the exocylic amino group of the purine ring.…”

Section: Transition-state Modelingmentioning

confidence: 99%

Transition state analysis of adenosine nucleosidase from yellow lupin (Lupinus luteus)

et al. 2006

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ChemInform Abstract: BOND ORDER METHODS FOR CALCULATING ISOTOPE EFFECTS IN ORGANIC REACTIONS

Cited by 7 publications

References 0 publications

Computational Study of Tunneling and Coupled Motion in Alcohol Dehydrogenase-Catalyzed Reactions: Implication for Measured Hydrogen and Carbon Isotope Effects

Computational Study of Tunneling and Coupled Motion in Alcohol Dehydrogenase-Catalyzed Reactions: Implication for Measured Hydrogen and Carbon Isotope Effects

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Transition state analysis of adenosine nucleosidase from yellow lupin (Lupinus luteus)

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