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

Research output: Contribution to journalArticle (Academic Journal)

Original languageEnglish
Pages (from-to)11303-14
Number of pages12
JournalJournal of Physical Chemistry B
Issue number34
DatePublished - 2 Sep 2010


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.

    Research areas

  • Quantum Theory, Thermodynamics, Protons, Models, Molecular, Acetyl Coenzyme A, Citrate (si)-Synthase, Models, Biological, Biocatalysis



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