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.
authors.affiliation: Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
authors.forename: Marc W
authors.initials: MW
authors.lastname: van der Kamp
authors.forename: Jolanta
authors.initials: J
authors.lastname: Zurek
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Manby
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Harvey
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
mesh_terms: D000105:Acetyl Coenzyme A / Q000737:chemistry*; D055162:Biocatalysis; D002950:Citrate (si)-Synthase / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D011522:Protons; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D011522:Protons; D000105:Acetyl Coenzyme A; D002950:Citrate (si)-Synthase