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Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase

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Testing high-level QM/MM methods for modeling enzyme reactions : acetyl-CoA deprotonation in citrate synthase. / van der Kamp, Marc W; Zurek, Jolanta; Manby, Frederick R; Harvey, Jeremy N; Mulholland, Adrian J.

In: Journal of Physical Chemistry B, Vol. 114, No. 34, 02.09.2010, p. 11303-14.

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van der Kamp, Marc W ; Zurek, Jolanta ; Manby, Frederick R ; Harvey, Jeremy N ; Mulholland, Adrian J. / Testing high-level QM/MM methods for modeling enzyme reactions : acetyl-CoA deprotonation in citrate synthase. In: Journal of Physical Chemistry B. 2010 ; Vol. 114, No. 34. pp. 11303-14.

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@article{4b217213abe24f4799f1a363f4805e2a,
title = "Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase",
abstract = "Combined quantum mechanics/molecular mechanics (QM/MM) calculations with high levels of correlated ab initio theory can now provide benchmarks for enzyme-catalyzed reactions. Here, we use such methods to test various QM/MM methods and the sensitivity of the results to details of the models for an important enzyme reaction, proton abstraction from acetyl-coenzyme A in citrate synthase. We calculate multiple QM/MM potential energy surfaces up to the local coupled cluster theory (LCCSD(T0)) level, with structures optimized at hybrid density functional theory and Hartree-Fock levels. The influence of QM methods, basis sets, and QM region size is shown to be significant. Correlated ab initio QM/MM calculations give barriers in agreement with experiment for formation of the acetyl-CoA enolate intermediate. In contrast, B3LYP fails to identify the enolate as an intermediate, whereas BH&HLYP does. The results indicate that QM/MM methods and setup should be tested, ideally using high-level calculations, to draw reliable mechanistic conclusions.",
keywords = "Quantum Theory, Thermodynamics, Protons, Models, Molecular, Acetyl Coenzyme A, Citrate (si)-Synthase, Models, Biological, Biocatalysis",
author = "{van der Kamp}, {Marc W} and Jolanta Zurek and Manby, {Frederick R} and Harvey, {Jeremy N} and Mulholland, {Adrian J}",
year = "2010",
month = "9",
day = "2",
doi = "10.1021/jp104069t",
language = "English",
volume = "114",
pages = "11303--14",
journal = "Journal of Physical Chemistry B",
issn = "1520-6106",
publisher = "American Chemical Society",
number = "34",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Testing high-level QM/MM methods for modeling enzyme reactions

T2 - acetyl-CoA deprotonation in citrate synthase

AU - van der Kamp, Marc W

AU - Zurek, Jolanta

AU - Manby, Frederick R

AU - Harvey, Jeremy N

AU - Mulholland, Adrian J

PY - 2010/9/2

Y1 - 2010/9/2

N2 - Combined quantum mechanics/molecular mechanics (QM/MM) calculations with high levels of correlated ab initio theory can now provide benchmarks for enzyme-catalyzed reactions. Here, we use such methods to test various QM/MM methods and the sensitivity of the results to details of the models for an important enzyme reaction, proton abstraction from acetyl-coenzyme A in citrate synthase. We calculate multiple QM/MM potential energy surfaces up to the local coupled cluster theory (LCCSD(T0)) level, with structures optimized at hybrid density functional theory and Hartree-Fock levels. The influence of QM methods, basis sets, and QM region size is shown to be significant. Correlated ab initio QM/MM calculations give barriers in agreement with experiment for formation of the acetyl-CoA enolate intermediate. In contrast, B3LYP fails to identify the enolate as an intermediate, whereas BH&HLYP does. The results indicate that QM/MM methods and setup should be tested, ideally using high-level calculations, to draw reliable mechanistic conclusions.

AB - Combined quantum mechanics/molecular mechanics (QM/MM) calculations with high levels of correlated ab initio theory can now provide benchmarks for enzyme-catalyzed reactions. Here, we use such methods to test various QM/MM methods and the sensitivity of the results to details of the models for an important enzyme reaction, proton abstraction from acetyl-coenzyme A in citrate synthase. We calculate multiple QM/MM potential energy surfaces up to the local coupled cluster theory (LCCSD(T0)) level, with structures optimized at hybrid density functional theory and Hartree-Fock levels. The influence of QM methods, basis sets, and QM region size is shown to be significant. Correlated ab initio QM/MM calculations give barriers in agreement with experiment for formation of the acetyl-CoA enolate intermediate. In contrast, B3LYP fails to identify the enolate as an intermediate, whereas BH&HLYP does. The results indicate that QM/MM methods and setup should be tested, ideally using high-level calculations, to draw reliable mechanistic conclusions.

KW - Quantum Theory

KW - Thermodynamics

KW - Protons

KW - Models, Molecular

KW - Acetyl Coenzyme A

KW - Citrate (si)-Synthase

KW - Models, Biological

KW - Biocatalysis

U2 - 10.1021/jp104069t

DO - 10.1021/jp104069t

M3 - Article

VL - 114

SP - 11303

EP - 11314

JO - Journal of Physical Chemistry B

JF - Journal of Physical Chemistry B

SN - 1520-6106

IS - 34

ER -