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

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 in COMT exhibit limited variations with respect to the size of the QM region, which ranges from ∼100 to ∼500 atoms in this study. With extensive sampling, local and global structural characteristics of the enzyme are largely conserved across the studied QM regions, while the nature of the transition state (e.g., secondary kinetic isotope effect) and reaction exergonicity are largely maintained. Deviations in the free energy profile with different QM region sizes are similar in magnitude to those observed with changes in other simulation protocols, such as different initial enzyme conformations and boundary conditions. Electronic structural properties, such as the covariance matrix of residual charge fluctuations, appear to exhibit rather long-range correlations, especially when the peptide backbone is included in the QM region; this observation holds when 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.

Improving the Accuracy of Quantum Mechanics/Molecular Mechanics (QM/MM) Models with Polarized Fragment Charges

“…To further complicate matters, the QM region can be defined using different schemes ( e.g ., based on the distance from the reaction center, atomic charges, or chemical intuition), and the QM/MM models may be implemented using different pairings of QM methods and MM potentials, choice of embedding scheme, methods to treat the QM/MM boundary, and whether periodic boundary conditions are used. , Additionally, QM/MM energies may be calculated based on static geometries derived from crystal structures or an ensemble of configurations sampled from molecular dynamics simulations. − These choices could affect the accuracy and convergence of QM/MM reaction barriers and energies with respect to the QM region size and may explain some of the conflicting observations made by different research groups regarding the convergence behavior of their QM/MM models. ,, Notably, the catechol- O -methyltransferase (COMT) enzyme has been used as a model system by several groups to study the effect of the QM region size on the calculated reaction barriers and energies. ,,,− The most recent study by Cui and co-workers indicates that with extensive configurational sampling, the structural characteristics and energetics of the enzymatic reaction become less sensitive to the QM region size . However, due to the high computational cost of these studies, they are invariably limited to a specific QM and MM pairing ( e.g,.…”

“…To further complicate matters, the QM region can be defined using different schemes (e.g., based on the distance from the reaction center, atomic charges, or chemical intuition), and the QM/MM models may be implemented using different pairings of QM methods and MM potentials, choice of embedding scheme, methods to treat the QM/MM boundary, and whether periodic boundary conditions are used. 10,11 Additionally, QM/MM energies may be calculated based on static geometries derived from crystal structures or an ensemble of configurations sampled from molecular dynamics simulations. 12−19 These choices could affect the accuracy and convergence of QM/MM reaction barriers and energies with respect to the QM region size and may explain some of the conflicting observations made by different research groups regarding the convergence behavior of their QM/MM models.…”

“…5,6,11,22−25 recent study by Cui and co-workers indicates that with extensive configurational sampling, the structural characteristics and energetics of the enzymatic reaction become less sensitive to the QM region size. 11 However, due to the high computational cost of these studies, they are invariably limited to a specific QM and MM pairing (e.g,. DFTB3-D3/ CHARMM, 11 ωPBEh/6-31G(d)/ff14SB, 22 and PM6/ENZY-MIX 6 have been used to simulate the COMT enzyme) and a specific system, so it is unclear whether these results may be carried over to different systems and/or implementations of QM/MM models.…”

“…11 However, due to the high computational cost of these studies, they are invariably limited to a specific QM and MM pairing (e.g,. DFTB3-D3/ CHARMM, 11 ωPBEh/6-31G(d)/ff14SB, 22 and PM6/ENZY-MIX 6 have been used to simulate the COMT enzyme) and a specific system, so it is unclear whether these results may be carried over to different systems and/or implementations of QM/MM models. At this point, it is important to emphasize that since QM/MM models are ultimately approximations of the direct QM treatment of the full system, their accuracy should be assessed against the latter instead of experimental data.…”

Convergence in Determining Enzyme Functional Descriptors across Kemp Eliminase Variants

“…This issue is particularly significant for QM-based calculations due to their high computational cost. Benchmarks have been performed to investigate the selection of QM regions that converge the computation of electronic structure descriptors (e.g., partial charge, [63][64][65][66][67] charge transfer, 67 charge density, 66 bond valence, 67 and electrostatic potential), energetic properties (e.g., energy barrier, reaction energy, and free energy), 64,65,[67][68][69][70][71][72][73][74][75] geometries, 64,73,74 and NMR shielding 76,77 in various model enzymes (peroxidase, methyltransferases, cytochrome P450, and deacetylase). 67 Rational QM region selection approaches have also been developed, including charge shift analysis, 78 Fukui shift analysis, 78 and point charge variation analysis 79 .…”