The effect of MM polarization on the QM/MM transition state stabilization: application to chorismate mutase

Illingworth, Christopher J. R.; Parkes, K. E. B.; Snell, Christopher R.; Martí, Sérgio; Moliner, Vicent; Reynolds, Christopher A.

doi:10.1080/00268970802077850

Cited by 18 publications

(22 citation statements)

References 30 publications

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“…For the fourth experiment, a QM/MM calculation was carried out on the ligand in its crystallographic position, with the QM region defined as the ligand, and the MM region defined as all residues of the protein with at least one atom within 5.5 Å of the ligand, the MM region being represented as point charges. Though it is true that the energetic effects of polarization will extend beyond this cutoff, 58 the effect of polarization on the magnitude of individual charges is generally short-ranged. 45 Therefore, for the purposes of assessing the effect of incorporating polarization into an MM docking model, a 5.5 Å residue-based cutoff is justified.…”

Section: Methodsmentioning

confidence: 99%

Assessing the Role of Polarization in Docking

et al. 2008

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We describe a strategy for including ligand and protein polarization in docking that is based on the conversion of induced dipoles to induced charges. Induced charges have a distinct advantage in that they are readily implemented into a number of different computer programs, including many docking programs and hybrid QM/MM programs; induced charges are also more readily interpreted. In this study, the ligand was treated quantum mechanically to avoid parametrization issues and was polarized by the target protein, which was treated as a set of point charges. The induced dipole at a given target atom, due to polarization by the ligand and neighboring residues, was reformulated as induced charges at the given atom and its bonded neighbors, and these were allowed to repolarize the ligand in an iterative manner. The final set of polarized charges was evaluated in docking using AutoDock 4.0 on 12 protein-ligand systems against the default empirical Gasteiger charges, and against nonpolarized and partially polarized potential-derived charges. One advantage of AutoDock is that the best rmsd structure can be identified not only from the lowest energy pose but also from the largest cluster of poses. Inclusion of polarization does not always lead to the lowest energy pose having a lower rmsd, because docking is designed by necessity to be rapid rather than accurate. However, whenever an improvement in methodology, corresponding to a more thorough treatment of polarization, resulted in an increased cluster size, then there was also a corresponding decrease in the rmsd. The options for implementing polarization within a purely classical docking framework are discussed.2008112

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Section: Methodsmentioning

confidence: 99%

Assessing the Role of Polarization in Docking

et al. 2008

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“…Several QM/MM calculations have been performed for free energy with explicit polarization included. [7][8][9][10][11][12][13][14] Acevedo and Jorgensen studied the Menshutkin reaction by a) Electronic mail: yamamoto@kuchem.kyoto-u.ac.jp. performing semiempirical QM/MM calculation with a polarizable OPLS model.…”

Section: Introductionmentioning

confidence: 99%

Variational calculation of quantum mechanical/molecular mechanical free energy with electronic polarization of solvent

Nakano

Yamamoto

2012

The Journal of Chemical Physics

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Quantum mechanical/molecular mechanical (QM/MM) free energy calculation presents a significant challenge due to an excessive number of QM calculations. A useful approach for reducing the computational cost is that based on the mean field approximation to the QM subsystem. Here, we describe such a mean-field QM/MM theory for electronically polarizable systems by starting from the Hartree product ansatz for the total system and invoking a variational principle of free energy. The MM part is then recast to a classical polarizable model by introducing the charge response kernel. Numerical test shows that the potential of mean force (PMF) thus obtained agrees quantitatively with that obtained from a direct QM/MM calculation, indicating the utility of self-consistent mean-field approximation. Next, we apply the obtained method to prototypical reactions in several qualitatively different solvents and make a systematic comparison of polarization effects. The results show that in aqueous solution the PMF does not depend very much on the water models employed, while in nonaqueous solutions the PMF is significantly affected by explicit polarization. For example, the free energy barrier for a phosphoryl dissociation reaction in acetone and cyclohexane is found to increase by more than 10 kcal/mol when switching the solvent model from an empirical to explicitly polarizable one. The reason for this is discussed based on the parametrization of empirical nonpolarizable models.

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“…Early approaches to the PE method involved simple iterations over an electrostatic embedding scheme where the inducible dipoles could be back-polarized by point charges fit to the electronic density until the system converged. [11][12][13][14] A related approximation to the polarizable embedding was introduced with the LICHEM interface, which couples generic QM and MM software using a partially self-consistent polarization scheme, compromising some accuracy for a more generalized interface and grater computational efficiency. 15,16 By solving the QM equations and the MM polarization equations in a fully coupled fashion, some recent approaches adopt a more intimate coupling between the electron density in the QM region and the polarization in the MM region, with the latter being modeled by inducible point dipoles (IPD), [17][18][19][20][21][22][23][24][25] fluctuating charges, [26][27][28][29][30][31] Drude oscillators., [32][33][34][35][36][37] or using a response kernel.…”

Section: Introductionmentioning

confidence: 99%

A Many-Body, Fully Polarizable Approach to QM/MM Simulations

Lambros¹,

Lipparini²,

Cisneros³

et al. 2020

Preprint

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<div> <div> <div> <p>We present a new development in quantum mechanics/molecular mechanics (QM/MM) methods by replacing conventional MM models with data-driven many-body (MB) representations rigorously derived from high-level QM calculations. The new QM/MM approach builds on top of mutually polarizable QM/MM schemes developed for polarizable force fields with inducible dipoles and uses permutationally invariant polynomials to effectively account for quantum- mechanical contributions (e.g., exchange-repulsion, and charge transfer and penetration) that are difficult to describe by classical expressions adopted by conventional MM models. Us- ing the many-body MB-pol and MB-DFT potential energy functions for water, which include explicit 2-body and 3-body terms fitted to reproduce the corresponding CCSD(T) and PBE0 2- body and 3-body energies for water, we demonstrate a smooth energetic transition as molecules are transferred between QM and MM regions, without the need of a transition layer. By effectively elevating the accuracy of both the MM region and the QM/MM interface to that of the QM region, the new QM/MB-MM approach achieves an accuracy comparable to that obtained with a fully QM treatment of the entire system. </p> </div> </div> </div>

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The effect of MM polarization on the QM/MM transition state stabilization: application to chorismate mutase

Cited by 18 publications

References 30 publications

Assessing the Role of Polarization in Docking

Assessing the Role of Polarization in Docking

Variational calculation of quantum mechanical/molecular mechanical free energy with electronic polarization of solvent

A Many-Body, Fully Polarizable Approach to QM/MM Simulations

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