An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

Huang, Jing; Ye, Mei; König, Gerhard; Simmonett, Andrew C.; Pickard, Frank C.; Wu, Qin; Wang, Lee‐Ping; MacKerell, Alexander D.; Brooks, Bernard R.; Shao, Yihan

doi:10.1021/acs.jctc.6b01125

Cited by 20 publications

(23 citation statements)

References 112 publications

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“…while QM/MM calculations with about 30 gold atoms treated at the QM level qualitatively agree with periodic DFT calculations in the gas-phase, there are also quantitative differences in terms of energetics and charge distributions (see Tables 2 and 3). Future efforts to better couple QM with polarizable MM [74][75][76] will further improve the quantitative accuracy of QM/MM simulations for materials/solution interfaces.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the conformational properties of amine ligands at the gold/water interface with QM, MM and QM/MM simulations

Liang

Hong

Dong

et al. 2018

Phys. Chem. Chem. Phys.

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We describe a strategy of integrating quantum mechanical (QM), hybrid quantum mechanical/molecular mechanical (QM/MM) and MM simulations to analyze the physical properties of a solid/water interface. This protocol involves using a correlated ab initio (CCSD(T)) method to first calibrate Density Functional Theory (DFT) as the QM approach, which is then used in QM/MM simulations to compute relevant free energy quantities at the solid/water interface using a mean-field approximation of Yang et al. that decouples QM and MM thermal fluctuations; gas-phase QM/MM and periodic DFT calculations are used to determine the proper QM size in the QM/MM simulations. Finally, the QM/MM free energy results are compared with those obtained from MM simulations to directly calibrate the force field model for the solid/water interface. This protocol is illustrated by examining the orientations of an alkyl amine ligand at the gold/water interface, since the ligand conformation is expected to impact the chemical properties (e.g., charge) of the solid surface. DFT/MM and MM simulations using the INTERFACE force field lead to consistent results, suggesting that the effective gold/ligand interactions can be adequately described by a van der Waals model, while electrostatic and induction effects are largely quenched by solvation. The observed differences among periodic DFT, QM/MM and MM simulations, nevertheless, suggest that explicitly including electronic polarization and potentially charge transfer in the MM model can be important to the quantitative accuracy. The strategy of integrating multiple computational methods to cross-validate each other for complex interfaces is applicable to many problems that involve both inorganic/metallic and organic/biomolecular components, such as functionalized nanoparticles.

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Section: Discussionmentioning

confidence: 99%

Analysis of the conformational properties of amine ligands at the gold/water interface with QM, MM and QM/MM simulations

Liang

Hong

Dong

et al. 2018

Phys. Chem. Chem. Phys.

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“…According to the linear response theory, a simple derivation of the IPolQ‐Mod charges are given in the Supporting Information. The IPolQ‐Mod method has been used to calculate the solvation free energy in recent studies .…”

Section: Methodsmentioning

confidence: 99%

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

Jia

2019

J Comput Chem

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The IPolQ‐Mod charges, which are the average of two charge sets fitted in vacuum state and condensed phase, take account of polarization effect implicitly in the solvation free energy calculation. However, the performance of the IPolQ‐Mod charges sensitively depends on the QM levels used to generate the electrostatic potential from which the charges are fitted. In addition, the forces on atoms are not accurate theoretically in the molecular dynamics (MD) simulation as the solvent only feels the electrostatic potential of a half‐polarized density of the solute according to the derivation of the IPolQ‐Mod charges. To study these issues in detail, the IPolQ‐Mod charges are combined with the reference potential (RP) strategy to predict the solvation free energies in the present study. It is found that the thermodynamic perturbation (TP) corrections utilizing total energy difference and interaction energy difference are almost the same and free of bias. The solvation free energies estimated by the RP method match very well with those obtained by applying IPolQ‐Mod charges into MD simulation directly. By means of the RP strategy, the performances of the IPolQ‐Mod charges with the change of the strength of the exact HF exchange in several DFT functionals are determined effectively. Although the “optimal” strengths are found in B3LYP and LC‐ωPBE, the improvements over the default strength are not too much. In addition to the IPolQ‐Mod charges, other charge models like bond charge correction (BCC) charges could also be combined with the RP strategy to study the thermodynamic properties like solvation free energy. © 2019 Wiley Periodicals, Inc.

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“…This particular choice was made to simplify the description and avoid calculations on intramolecular interactions. 96,97 We performed four QM<->MM transformation calculations for each state along the binding pathway (using different starting structures from the enhanced sampling MD simulations). Each transformation consists of2.5 million MC moves in the MM Hamiltonian per lambda window and a total of 50 QM energy evaluations per lambda window.…”

Section: Methodsmentioning

confidence: 99%

A Multiscale Simulation Approach to Modeling Drug–Protein Binding Kinetics

Haldar

Comitani

Saladino

et al. 2018

J. Chem. Theory Comput.

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Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simulations can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the binding kinetics, but significant challenges include the long time scales involved in (un)binding events and the limited accuracy of empirical atomistic force fields (lacking, e.g., changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechanics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterize the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug Imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mechanism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in binding of ligands to protein targets.

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An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

Cited by 20 publications

References 112 publications

Analysis of the conformational properties of amine ligands at the gold/water interface with QM, MM and QM/MM simulations

Analysis of the conformational properties of amine ligands at the gold/water interface with QM, MM and QM/MM simulations

Solvation Free Energy Calculations: The Combination between the Implicitly Polarized Fixed‐charge Model and the Reference Potential Strategy

A Multiscale Simulation Approach to Modeling Drug–Protein Binding Kinetics

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