Semiempirical calculations of the oxygen equilibrium isotope effect on binding of oxamate to lactate dehydrogenase

Gawlita, Ewa; Anderson, Vernon E.; Paneth, Piotr

doi:10.1007/bf00188659

Cited by 10 publications

(8 citation statements)

References 13 publications

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“…As binding usually involves weak, noncovalent interactions, these isotope effects were for many years neglected. Only a few studies have been aimed directly or indirectly , at kinetic isotope effects on binding. In the remaining part of this Review, we will discuss only equilibrium isotope effects on binding and we will be using the BIE symbol to denote them.…”

Section: Isotope Effectsmentioning

confidence: 99%

Binding Isotope Effects

Świderek

Paneth

2013

Chem. Rev.

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Section: Isotope Effectsmentioning

confidence: 99%

Binding Isotope Effects

Świderek

Paneth

2013

Chem. Rev.

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“…In the mid 90s, we studied the oxygen isotope effect of oxamate carboxylic oxygen atoms on its binding to lactic dehydrogenase both experimentally and theoretically . These studies showed that changes in the hydrogen bonding network between the aqueous solution and LDH enzyme active site can lead to significant binding isotope effects (BIEs).…”

Section: Introductionmentioning

confidence: 99%

“…In the mid 90s, we studied the oxygen isotope effect of oxamate carboxylic oxygen atoms on its binding to lactic dehydrogenase both experimentally 18 and theoretically. 19 These studies showed that changes in the hydrogen bonding network between the aqueous solution and LDH enzyme active site can lead to significant binding isotope effects (BIEs). With the above-mentioned applications of LDH in diagnostics, BIEs may prove to be very useful means of determinations of the conformation and type of different LDH isozymes.…”

Section: Introductionmentioning

confidence: 99%

Modeling of Isotope Effects on Binding Oxamate to Lactic Dehydrogenase

et al. 2009

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A new crystal structure of the rabbit muscle L-lactic dehydrogenase (PDB code 3H3F) has been determined. The independent unit of this structure contains two tetramers, each of them with a unique constitution of two active sites with the open loop conformation and two with the loops closed over the actives sites. On the basis of this structure, interactions of an inhibitor, oxamate anion, with the protein have been modeled using different hybrid schemes that involved B3LYP/6-31++G(d,p) DFT theory level in the QM layer. In ONIOM calculations, either Amber (QM:MM) or one of the three semiempirical parametrizations, AM1, PM3, and RM1 (QM:QM) was used, while in the traditional QM/MM scheme, the OPLS-AA force field was used for the outer layer. Normal modes of vibrations of oxamate in aqueous solution and in the active site of the enzyme were used to calculate binding isotope effects. On the basis of the comparison of the values obtained theoretically with those experimentally determined for the oxygen atoms of the carboxylic group of oxamate it was concluded that the DFT/OPLS-AA scheme, applied to the dimer consisting of two chains, one with the open loop and the other with the closed loop conformation, provides the best description of the active site. Calculations of the binding isotope effects of the other atoms of oxamate suggest that nitrogen isotope effect may be useful for the experimental differentiation between open and closed loop conformations.

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“…where superscripts r and p refer to reactant and product isotopomers, respectively. Usually, equilibrium isotope effects are computed only approximately: 1,2,3,4,5,6,7,8,9,10,11,12,13 In particular, effects due to indistinguishability of particles and rotational and vibrational contributions to the EIE are treated separately. Furthermore, the vibrational motion is approximated by a simple harmonic oscillator and the rotational motion is approximated by a rigid rotor.…”

Section: Introductionmentioning

confidence: 99%

Path integral evaluation of equilibrium isotope effects

Zimmermann

Vaníček

2009

The Journal of Chemical Physics

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A general and rigorous methodology to compute the quantum equilibrium isotope effect is described. Unlike standard approaches, ours does not assume separability of rotational and vibrational motions and does not make the harmonic approximation for vibrations or rigid rotor approximation for the rotations. In particular, zero point energy and anharmonicity effects are described correctly quantum mechanically. The approach is based on the thermodynamic integration with respect to the mass of isotopes and on the Feynman path integral representation of the partition function. An efficient estimator for the derivative of free energy is used whose statistical error is independent of the number of imaginary time slices in the path integral, speeding up calculations by a factor of ϳ60 at 500 K and more at room temperature. We describe the implementation of the methodology in the molecular dynamics package AMBER 10. The method is tested on three ͓1,5͔ sigmatropic hydrogen shift reactions. Because of the computational expense, we use ab initio potentials to evaluate the equilibrium isotope effects within the harmonic approximation and then the path integral method together with semiempirical potentials to evaluate the anharmonicity corrections. Our calculations show that the anharmonicity effects amount up to 30% of the symmetry reduced reaction free energy. The numerical results are compared with recent experiments of Doering et al., ͓J. Am. Chem. Soc. 128, 9080 ͑2006͒; 129, 2488 ͑2007͔͒ confirming the accuracy of the most recent measurement on 2,4,6,7,9-pentamethyl-5-͑5,5-2 H 2 ͒methylene-11,11a-dihydro-12H-naphthacene as well as concerns about compromised accuracy, due to side reactions, of another measurement on 2-methyl-10-͑10,10-2 H 2 ͒methylenebicyclo͓4.4.0͔dec-1-ene.

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Semiempirical calculations of the oxygen equilibrium isotope effect on binding of oxamate to lactate dehydrogenase

Cited by 10 publications

References 13 publications

Binding Isotope Effects

Binding Isotope Effects

Modeling of Isotope Effects on Binding Oxamate to Lactic Dehydrogenase

Path integral evaluation of equilibrium isotope effects

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