Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

• Published in: Journal of chemical information and modeling Vol. 59; no. 5; pp. 2063 - 2078
• Main Authors: Ranaghan, Kara E, Shchepanovska, Darya, Bennie, Simon J, Lawan, Narin, Macrae, Stephen J, Zurek, Jolanta, Manby, Frederick R, Mulholland, Adrian J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.05.2019
• Subjects: Catalytic Domain; Chorismate Mutase - chemistry; Chorismate Mutase - metabolism; Density; Density Functional Theory; Dependence; Embedded systems; Embedding; Enzymes; Enzymes - chemistry; Enzymes - metabolism; Mathematical analysis; Models, Molecular; Quantum mechanics; Thermodynamics
• DOI: 10.1021/acs.jcim.8b00940
• ISSN: 1549-9596; 1549-960X

Combined quantum mechanics/molecular mechanics (QM/MM) methods are increasingly widely utilized in studies of reactions in enzymes and other large systems. Here, we apply a range of QM/MM methods to investigate the Claisen rearrangement of chorismate to prephenate, in solution, and in the enzyme chorismate mutase. Using projector-based embedding in a QM/MM framework, we apply treatments up to the CCSD­(T) level. We test a range of density functional QM/MM methods and QM region sizes. The results show that the calculated reaction energetics are significantly more sensitive to the choice of density functional than they are to the size of the QM region in these systems. Projector-based embedding of a wave function method in DFT reduced the 13 kcal/mol spread in barrier heights calculated at the DFT/MM level to a spread of just 0.3 kcal/mol, essentially eliminating dependence on the functional. Projector-based embedding of correlated ab initio methods provides a practical method for achieving high accuracy for energy profiles derived from DFT and DFT/MM calculations for reactions in condensed phases.