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Incorporation of a QM/MM buffer zone in the variational double self-consistent field method.

ABSTRACT: The explicit polarization (X-Pol) potential is an electronic-structure-based polarization force field, designed for molecular dynamics simulations and modeling of biopolymers. In this approach, molecular polarization and charge transfer effects are explicitly treated by a combined quantum mechanical and molecular mechanical (QM/MM) scheme, and the wave function of the entire system is variationally optimized by a double self-consistent field (DSCF) method. In the present article, we introduce a QM buffer zone for a smooth transition from a QM region to an MM region. Instead of using the Mulliken charge approximation for all QM/MM interactions, the Coulombic interactions between the adjacent fragments are determined directly by electronic structure theory. The present method is designed to accelerate the speed of convergence of the total energy and charge density of the system.

SUBMITTER: Xie W

PROVIDER: S-EPMC2725410 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Incorporation of a QM/MM buffer zone in the variational double self-consistent field method.

Xie Wangshen W Song Lingchun L Truhlar Donald G DG Gao Jiali J

The journal of physical chemistry. B 20081021 45

The explicit polarization (X-Pol) potential is an electronic-structure-based polarization force field, designed for molecular dynamics simulations and modeling of biopolymers. In this approach, molecular polarization and charge transfer effects are explicitly treated by a combined quantum mechanical and molecular mechanical (QM/MM) scheme, and the wave function of the entire system is variationally optimized by a double self-consistent field (DSCF) method. In the present article, we introduce a ...[more]

PMID: 18937511

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Project description:Design of selective ligands for closely related targets is becoming one of the most important tasks in the drug development. New tools, more precise than fast scoring functions and less demanding than sophisticated Free Energy Perturbation methods, are necessary to help accomplish this goal. The methods of intermediate complexity, characterizing individual contributions to the binding energy, have been an area of intense research in the past few years. Our recently developed quantum mechanical/molecular mechanical (QM/MM) modification of the Linear Response (LR) method describes the binding free energies as the sum of empirically weighted contributions of the QM/MM interaction energies and solvent-accessible surface areas for the time-averaged structures of hydrated complexes, obtained by molecular dynamics (MD) simulations. The method was applied to published data on 27 inhibitors of matrix metalloproteinase-3 (MMP-3). The two descriptors explained 90% of variance in the inhibition constants with RMSE of 0.245 log units. The QM/MM treatment is indispensable for characterization of the systems lacking suitable force-field expressions. In this case, it provided characteristics of H-bonds of the inhibitors to Glu202, charges of binding site atoms, and accurate coordination geometries of the ligands to catalytic zinc. The geometries were constrained during the MD simulations, which characterized conformational flexibility of the complexes and helped in the elucidation of the binding differences for related compounds. A comparison of the presented QM/MM LR results with those previously published for inhibition of MMP-9 by the same set of ligands showed that the QM/MM LR approach was able to distinguish subtle differences in binding affinities for MMP-3 and MMP-9, which did not exceed one order of magnitude. This precision level makes the approach a useful tool for design of selective ligands to similar targets, because the results can be safely extrapolated to maximize selectivity.

Project description:THE RELIABILITY OF FREE ENERGY SIMULATIONS (FES) IS LIMITED BY TWO FACTORS: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Dataset Information

Incorporation of a QM/MM buffer zone in the variational double self-consistent field method.

Publications

Incorporation of a QM/MM buffer zone in the variational double self-consistent field method.

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