Dataset Information

Automated Fragmentation QM/MM Calculation of NMR Chemical Shifts for Protein-Ligand Complexes.

ABSTRACT: In this study, the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) method was applied for NMR chemical shift calculations of protein-ligand complexes. In the AF-QM/MM approach, the protein binding pocket is automatically divided into capped fragments (within ~200 atoms) for density functional theory (DFT) calculations of NMR chemical shifts. Meanwhile, the solvent effect was also included using the Poission-Boltzmann (PB) model, which properly accounts for the electrostatic polarization effect from the solvent for protein-ligand complexes. The NMR chemical shifts of neocarzinostatin (NCS)-chromophore binding complex calculated by AF-QM/MM accurately reproduce the large-sized system results. The 1H chemical shift perturbations (CSP) between apo-NCS and holo-NCS predicted by AF-QM/MM are also in excellent agreement with experimental results. Furthermore, the DFT calculated chemical shifts of the chromophore and residues in the NCS binding pocket can be utilized as molecular probes to identify the correct ligand binding conformation. By combining the CSP of the atoms in the binding pocket with the Glide scoring function, the new scoring function can accurately distinguish the native ligand pose from decoy structures. Therefore, the AF-QM/MM approach provides an accurate and efficient platform for protein-ligand binding structure prediction based on NMR derived information.

SUBMITTER: Jin X

PROVIDER: S-EPMC5952040 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Automated Fragmentation QM/MM Calculation of NMR Chemical Shifts for Protein-Ligand Complexes.

Jin Xinsheng X Zhu Tong T Zhang John Z H JZH He Xiao X

Frontiers in chemistry 20180508

In this study, the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) method was applied for NMR chemical shift calculations of protein-ligand complexes. In the AF-QM/MM approach, the protein binding pocket is automatically divided into capped fragments (within ~200 atoms) for density functional theory (DFT) calculations of NMR chemical shifts. Meanwhile, the solvent effect was also included using the Poission-Boltzmann (PB) model, which properly accounts for the electrosta ...[more]

PMID: 29868556

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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

Automated Fragmentation QM/MM Calculation of NMR Chemical Shifts for Protein-Ligand Complexes.

Publications

Automated Fragmentation QM/MM Calculation of NMR Chemical Shifts for Protein-Ligand Complexes.

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