Dataset Information

Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.

ABSTRACT: Reliable prediction of binding affinities for ligand-receptor complex has been the primary goal of a structure-based drug design process. In this respect, alchemical methods are evolving as a popular choice to predict the binding affinities for biomolecular complexes. However, the highly flexible protein-ligand systems pose a challenge to the accuracy of binding free energy calculations mostly due to insufficient sampling. Herein, integrated computational protocol combining free energy perturbation based absolute binding free energy calculation with free energy landscape method was proposed for improved prediction of binding free energy for flexible protein-ligand complexes. The proposed method is applied to the dataset of various classes of p53-MDM2 (murine double minute 2) inhibitors. The absolute binding free energy calculations for MDMX (murine double minute X) resulted in a mean absolute error value of 0.816 kcal/mol while it is 3.08 kcal/mol for MDM2, a highly flexible protein compared to MDMX. With the integration of the free energy landscape method, the mean absolute error for MDM2 is improved to 1.95 kcal/mol.

SUBMITTER: Singh N

PROVIDER: S-EPMC7369993 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.

Singh Nidhi N Li Wenjin W

International journal of molecular sciences 20200704 13

Reliable prediction of binding affinities for ligand-receptor complex has been the primary goal of a structure-based drug design process. In this respect, alchemical methods are evolving as a popular choice to predict the binding affinities for biomolecular complexes. However, the highly flexible protein-ligand systems pose a challenge to the accuracy of binding free energy calculations mostly due to insufficient sampling. Herein, integrated computational protocol combining free energy perturbat ...[more]

PMID: 32635537

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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

Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.

Publications

Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.

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