Factors That Determine the Variation of Equilibrium and Kinetic Properties of QM/MM Enzyme Simulations: QM Region, Conformation, and Boundary Condition

Demapan, Darren; Kussmann, Joerg; Ochsenfeld, Christian und Cui, Qiang (2022): Factors That Determine the Variation of Equilibrium and Kinetic Properties of QM/MM Enzyme Simulations: QM Region, Conformation, and Boundary Condition. In: Journal of Chemical Theory and Computation, Bd. 18, Nr. 4: S. 2530-2542

Abstract

To analyze the impact of various technical details on the results of quantum mechanical (QM)/molecular mechanical (MM) enzyme simulations, including the QM region size, catechol-O-methyltransferase (COMT) is studied as a model system using an approximate QM/MM method (DFTB3/CHARMM).The results show that key equilibrium and kinetic properties for methyl transfer inCOMT exhibit limited variations with respect to the size of the QM region, which ranges from similar to 100 to similar to 500 atoms in this study. With extensive sampling, local andglobal structural characteristics of the enzyme are largely conserved across thestudied QM regions, while the nature of the transition state (e.g., secondary kineticisotope effect) and reaction exergonicity are largely maintained. Deviations in the free energy profile with different QM region sizesare similar in magnitude to those observed with changes in other simulation protocols, such as different initial enzyme conformationsand boundary conditions. Electronic structural properties, such as the covariance matrix of residual chargefluctuations, appear toexhibit rather long-range correlations, especially when the peptide backbone is included in the QM region;this observation holdswhen a range-separated DFT approach is used as the QM region, suggesting that delocalization error is unlikely the origin. Overall, the analyses suggest that multiple simulation details determine the results of QM/MM enzyme simulations with comparable contributions

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Chemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1549-9618
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 325871075