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Molecular dynamics free energy calculations to assess the possibility of water existence in protein nonpolar cavities.

ABSTRACT: Are protein nonpolar cavities filled with water molecules? Although many experimental and theoretical investigations have been done, particularly for the nonpolar cavity of IL-1 beta, the results are still conflicting. To study this problem from the thermodynamic point of view, we calculated hydration free energies of four protein nonpolar cavities by means of the molecular dynamics thermodynamic integration method. In addition to the IL-1 beta cavity (69 A(3)), we selected the three largest nonpolar cavities of AvrPphB (81 A(3)), Trp repressor (87 A(3)), and hemoglobin (108 A(3)) from the structural database, in view of the simulation result from another study that showed larger nonpolar cavities are more likely to be hydrated. The calculations were performed with flexible and rigid protein models. The calculated free energy changes were all positive; hydration of the nonpolar cavities was energetically unfavorable for all four cases. Because hydration of smaller cavities should happen more rarely, we conclude that existing protein nonpolar cavities are not likely to be hydrated. Although a possibility remains for much larger nonpolar cavities, such cases are not found experimentally. We present a hypothesis to explain this: hydrated nonpolar cavities are quite unstable and the conformation could not be maintained.

SUBMITTER: Oikawa M

PROVIDER: S-EPMC2884266 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Molecular dynamics free energy calculations to assess the possibility of water existence in protein nonpolar cavities.

Oikawa Masataka M Yonetani Yoshiteru Y

Biophysical journal 20100601 12

Are protein nonpolar cavities filled with water molecules? Although many experimental and theoretical investigations have been done, particularly for the nonpolar cavity of IL-1 beta, the results are still conflicting. To study this problem from the thermodynamic point of view, we calculated hydration free energies of four protein nonpolar cavities by means of the molecular dynamics thermodynamic integration method. In addition to the IL-1 beta cavity (69 A(3)), we selected the three largest non ...[more]

PMID: 20550910

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Project description:The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on" and "off." Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from approximately 25,000 to 2500. The computations are very efficient and the statistical error is small ( approximately 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within approximately 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.

Dataset Information

Molecular dynamics free energy calculations to assess the possibility of water existence in protein nonpolar cavities.

Publications

Molecular dynamics free energy calculations to assess the possibility of water existence in protein nonpolar cavities.

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