Dataset Information

Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: an evaluation in protein kinase and phosphatase systems.

ABSTRACT: Reliable prediction of protein-ligand docking pose requires proper account of induced fit effects. Treating both the ligand and the protein as flexible molecules is still challenging because many degrees of freedom are involved. Peptides are one type of ligand that are particularly difficult to study because of their extreme flexibility. In this study, we tested a molecular dynamics-based simulated-annealing cycling protocol in docking peptides to four protein kinases and two phosphatases using two implicit-solvent models: a distance-dependent dielectric model (epsilon(r) = 4r) and a version of the Generalized Born model termed GBMV. We found that the simpler epsilon(r) = 4r model identified docking pose better than the more expensive GBMV model. In addition, rescoring structures obtained from one implicit-solvent model with the other identified good docking poses for all six systems studied. Including protein energy in scoring also improved results.

SUBMITTER: Huang Z

PROVIDER: S-EPMC2785084 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Publications

Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: an evaluation in protein kinase and phosphatase systems.

Huang Zunnan Z Wong Chung F CF

The journal of physical chemistry. B 20091001 43

Reliable prediction of protein-ligand docking pose requires proper account of induced fit effects. Treating both the ligand and the protein as flexible molecules is still challenging because many degrees of freedom are involved. Peptides are one type of ligand that are particularly difficult to study because of their extreme flexibility. In this study, we tested a molecular dynamics-based simulated-annealing cycling protocol in docking peptides to four protein kinases and two phosphatases using ...[more]

PMID: 19845408

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Project description:In this study several commonly used implicit solvent models are compared with respect to their accuracy of estimating solvation energies of small molecules and proteins, as well as desolvation penalty in protein-ligand binding. The test set consists of 19 small proteins, 104 small molecules, and 15 protein-ligand complexes. We compared predicted hydration energies of small molecules with their experimental values; the results of the solvation and desolvation energy calculations for small molecules, proteins and protein-ligand complexes in water were also compared with Thermodynamic Integration calculations based on TIP3P water model and Amber12 force field. The following implicit solvent (water) models considered here are: PCM (Polarized Continuum Model implemented in DISOLV and MCBHSOLV programs), GB (Generalized Born method implemented in DISOLV program, S-GB, and GBNSR6 stand-alone version), COSMO (COnductor-like Screening Model implemented in the DISOLV program and the MOPAC package) and the Poisson-Boltzmann model (implemented in the APBS program). Different parameterizations of the molecules were examined: we compared MMFF94 force field, Amber12 force field and the quantum-chemical semi-empirical PM7 method implemented in the MOPAC package. For small molecules, all of the implicit solvent models tested here yield high correlation coefficients (0.87-0.93) between the calculated solvation energies and the experimental values of hydration energies. For small molecules high correlation (0.82-0.97) with the explicit solvent energies is seen as well. On the other hand, estimated protein solvation energies and protein-ligand binding desolvation energies show substantial discrepancy (up to 10kcal/mol) with the explicit solvent reference. The correlation of polar protein solvation energies and protein-ligand desolvation energies with the corresponding explicit solvent results is 0.65-0.99 and 0.76-0.96 respectively, though this difference in correlations is caused more by different parameterization and less by methods and indicates the need for further improvement of implicit solvent models parameterization. Within the same parameterization, various implicit methods give practically the same correlation with results obtained in explicit solvent model for ligands and proteins: e.g. correlation values of polar ligand solvation energies and the corresponding energies in the frame of explicit solvent were 0.953-0.966 for the APBS program, the GBNSR6 program and all models used in the DISOLV program. The DISOLV program proved to be on a par with the other used programs in the case of proteins and ligands solvation energy calculation. However, the solution of the Poisson-Boltzmann equation (APBS program) and Generalized Born method (implemented in the GBNSR6 program) proved to be the most accurate in calculating the desolvation energies of complexes.

Dataset Information

Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: an evaluation in protein kinase and phosphatase systems.

Publications

Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: an evaluation in protein kinase and phosphatase systems.

Similar Datasets

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