Dataset Information

Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes.

ABSTRACT: Molecular docking provides a computationally efficient way to predict the atomic structural details of protein-RNA interactions (PRI), but accurate prediction of the three-dimensional structures and binding affinities for PRI is still notoriously difficult, partly due to the unreliability of the existing scoring functions for PRI. MM/PBSA and MM/GBSA are more theoretically rigorous than most scoring functions for protein-RNA docking, but their prediction performance for protein-RNA systems remains unclear. Here, we systemically evaluated the capability of MM/PBSA and MM/GBSA to predict the binding affinities and recognize the near-native binding structures for protein-RNA systems with different solvent models and interior dielectric constants (?in). For predicting the binding affinities, the predictions given by MM/GBSA based on the minimized structures in explicit solvent and the GBGBn1 model with ?in = 2 yielded the highest correlation with the experimental data. Moreover, the MM/GBSA calculations based on the minimized structures in implicit solvent and the GBGBn1 model distinguished the near-native binding structures within the top 10 decoys for 117 out of the 148 protein-RNA systems (79.1%). This performance is better than all docking scoring functions studied here. Therefore, the MM/GBSA rescoring is an efficient way to improve the prediction capability of scoring functions for protein-RNA systems.

SUBMITTER: Chen F

PROVIDER: S-EPMC6097651 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes.

Chen Fu F Sun Huiyong H Wang Junmei J Zhu Feng F Liu Hui H Wang Zhe Z Lei Tailong T Li Youyong Y Hou Tingjun T

RNA (New York, N.Y.) 20180621 9

Molecular docking provides a computationally efficient way to predict the atomic structural details of protein-RNA interactions (PRI), but accurate prediction of the three-dimensional structures and binding affinities for PRI is still notoriously difficult, partly due to the unreliability of the existing scoring functions for PRI. MM/PBSA and MM/GBSA are more theoretically rigorous than most scoring functions for protein-RNA docking, but their prediction performance for protein-RNA systems remai ...[more]

PMID: 29930024

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Project description:Accurate prediction of hydration free energies is a key objective of any free energy method that is applied to modeling and understanding interactions in the aqueous phase. Inhomogeneous fluid solvation theory (IFST) is a statistical mechanical method for calculating solvation free energies by quantifying the effect of a solute acting as a perturbation to bulk water. IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed. In this study, we report the hydration free energies of six simple solutes calculated using IFST and independently using free energy perturbation (FEP). This facilitates a validation of IFST that is independent of the accuracy of the force field. The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol. However, sampling is a major issue that plagues IFST calculations and the results suggest that a histogram method may require prohibitively long simulations to achieve convergence of the entropies, for bin sizes which effectively capture the underlying probability distributions. Results also highlight the sensitivity of IFST to the reference interaction energy of a water molecule in bulk, with a difference of 0.01 kcal/mol changing the predicted hydration free energies by approximately 2.4 kcal/mol for the systems studied here. One of the major advantages of IFST over perturbation methods such as FEP is that the systems are spatially decomposed to consider the contribution of specific regions to the total solvation free energies. Visualizing these contributions can yield detailed insights into solvation thermodynamics. An insight from this work is the identification and explanation of regions with unfavorable free energy density relative to bulk water. These regions contribute unfavorably to the hydration free energy. Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential.

Dataset Information

Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes.

Publications

Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes.

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