Importance of MM Polarization in QM/MM Studies of Enzymatic Reactions: Assessment of the QM/MM Drude Oscillator Model

Ganguly, Abir; Boulanger, Eliot; Thiel, Walter

doi:10.1021/acs.jctc.7b00016

Cited by 45 publications

(53 citation statements)

References 61 publications

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“…Our results also corroborate the conclusions of a recent study by Ganguly, Boulanger and Thiel [ 185 ]. The effect of MM polarization via Drude particles on QM/MM hydration free energies is only moderate compared to the well-developed CHARMM fixed charge force field.…”

Section: Discussionsupporting

confidence: 93%

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes

et al. 2018

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Maintaining a proper balance between specific intermolecular interactions and non-specific solvent interactions is of critical importance in molecular simulations, especially when predicting binding affinities or reaction rates in the condensed phase. The most rigorous metric for characterizing solvent affinity are solvation free energies, which correspond to a transfer from the gas phase into solution. Due to the drastic change of the electrostatic environment during this process, it is also a stringent test of polarization response in the model. Here, we employ both the CHARMM fixed charge and polarizable force fields to predict hydration free energies of twelve simple solutes. The resulting classical ensembles are then reweighted to obtain QM/MM hydration free energies using a variety of QM methods, including MP2, Hartree–Fock, density functional methods (BLYP, B3LYP, M06-2X) and semi-empirical methods (OM2 and AM1 ). Our simulations test the compatibility of quantum-mechanical methods with molecular-mechanical water models and solute Lennard–Jones parameters. In all cases, the resulting QM/MM hydration free energies were inferior to purely classical results, with the QM/MM Drude force field predictions being only marginally better than the QM/MM fixed charge results. In addition, the QM/MM results for different quantum methods are highly divergent, with almost inverted trends for polarizable and fixed charge water models. While this does not necessarily imply deficiencies in the QM models themselves, it underscores the need to develop consistent and balanced QM/MM interactions. Both the QM and the MM component of a QM/MM simulation have to match, in order to avoid artifacts due to biased solute–solvent interactions. Finally, we discuss strategies to improve the convergence and efficiency of multi-scale free energy simulations by automatically adapting the molecular-mechanics force field to the target quantum method.

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Section: Discussionsupporting

confidence: 93%

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes

et al. 2018

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“…ligands and a few residues). [12][13][14] The use of small QM regions has motivated method development 10,[15][16][17][18][19][20][21][22][23][24] to minimize QM/MM boundary effects and to evaluate 25 how moving beyond conventional electrostatic embedding to advanced, polarizable, 18,[25][26][27][28][29][30] force field treatments may improve QM/MM descriptions. Even with these advances, larger QM region sizes may be necessary in order to describe charge transfer between MM residues and the QM active site.…”

Section: Introductionmentioning

confidence: 99%

Revealing quantum mechanical effects in enzyme catalysis with large-scale electronic structure simulation

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Revealing Quantum Mechanical Effects in Enzyme Catalysis with Large-Scale Electronic Structure Simulation

Yang¹,

Mehmood²,

Wang³

et al. 2018

Preprint

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<div><div><div><p>Enzymes have evolved to facilitate challenging reactions at ambient conditions with specificity seldom matched by other catalysts. Computational modeling provides valuable insight into catalytic mechanism, and the large size of enzymes mandates multi-scale, quantum mechanical-molecular mechanical (QM/MM) simulations. Although QM/MM plays an essential role in balancing simulation cost to enable sampling with full QM treatment needed to understand electronic structure in enzyme active sites, the relative importance of these two strategies for understanding enzyme mechanism is not well known. We explore challenges in QM/MM for studying the reactivity and stability of three diverse enzymes: i) Mg2+-dependent catechol O-methyltransferase (COMT), ii) radical enzyme choline trimethylamine lyase (CutC), and iii) DNA methyltransferase (DNMT1), which has structural Zn2+ binding sites. In COMT, strong non-covalent interactions lead to long range coupling of electronic structure properties across the active site, but the more isolated nature of the metallocofactor in DNMT1 leads to faster convergence of some properties. We quantify these effects in COMT by computing covariance matrices of by-residue electronic structure properties during dynamics and along the reaction coordinate. In CutC, we observe spontaneous bond cleavage following initiation events, highlighting the importance of sampling and dynamics. We use electronic structure analysis to quantify the relative importance of CHO and OHO non-covalent interactions in imparting reactivity. These three diverse cases enable us to provide some general recommendations regarding QM/MM simulation of enzymes.</p></div></div></div>

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Importance of MM Polarization in QM/MM Studies of Enzymatic Reactions: Assessment of the QM/MM Drude Oscillator Model

Cited by 45 publications

References 61 publications

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes

Revealing quantum mechanical effects in enzyme catalysis with large-scale electronic structure simulation

Revealing Quantum Mechanical Effects in Enzyme Catalysis with Large-Scale Electronic Structure Simulation

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