Dataset Information

MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex.

ABSTRACT: A generalization of the Moving-Domain Quantum Mechanics/Molecular Mechanics (MoD-QM/MM) hybrid method [Gascon, J. A.; Leung, S. S. F.; Batista, E. R.; Batista, V. S. J. Chem. Theory Comput. 2006, 2, 175-186] is introduced to provide a self-consistent computational protocol for structural refinement of extended systems. The method partitions the system into molecular domains that are iteratively optimized as quantum mechanical (QM) layers embedded in their surrounding molecular environment to obtain an ab initio quality description of the geometry and the molecular electrostatic potential of the extended system composed of those constituent fragments. The resulting methodology is benchmarked as applied to model systems that allow for full QM optimization as well as through refinement of the hydrogen bonding geometry in Oxytricha nova guanine quadruplex for which several studies have been reported, including the X-ray structure and NMR data. Calculations of (1)H NMR chemical shifts based on the gauge independent atomic orbital (GIAO) method and direct comparisons with experiments show that solvated MoD-QM/MM structures, sampled from explicit solvent molecular dynamics simulations, allow for NMR simulations in much improved agreement with experimental data than models based on the X-ray structure or those optimized using classical molecular mechanics force fields.

SUBMITTER: Ho J

PROVIDER: S-EPMC5304451 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex.

Ho Junming J Newcomer Michael B MB Ragain Christina M CM Gascon Jose A JA Batista Enrique R ER Loria J Patrick JP Batista Victor S VS

Journal of chemical theory and computation 20141008 11

A generalization of the Moving-Domain Quantum Mechanics/Molecular Mechanics (MoD-QM/MM) hybrid method [Gascon, J. A.; Leung, S. S. F.; Batista, E. R.; Batista, V. S. J. Chem. Theory Comput. 2006, 2, 175-186] is introduced to provide a self-consistent computational protocol for structural refinement of extended systems. The method partitions the system into molecular domains that are iteratively optimized as quantum mechanical (QM) layers embedded in their surrounding molecular environment to obt ...[more]

PMID: 26584390

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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.

Dataset Information

MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex.

Publications

MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex.

Similar Datasets

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