TY - JOUR
T1 - Testing high-level QM/MM methods for modeling enzyme reactions
T2 - Journal of Physical Chemistry B
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 -