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Assessing the performance of MM/PBSA and MM/GBSA methods. 7. Entropy effects on the performance of end-point binding free energy calculation approaches

Abstract

Entropy effect plays an important role in drug-target interactions, but the entropic contribution to ligand-binding affinity is often neglected by the end-point binding free energy calculation methods, such as MM/GBSA and MM/PBSA, due to the expensive computational cost of normal mode analysis (NMA). Here, we systematically investigated the entropy effects on the prediction power of MM/GBSA and MM/PBSA using >1500 protein-ligand systems and 6 representative AMBER force fields. Two computationally efficient methods, including NMA based on truncated structures and the interaction entropy approach, were used to estimate the entropic contributions to ligand-target binding free energies. In the aspect of the overall accuracy, for the minimized structures, in most cases the inclusion of the conformational entropies predicted by the truncated NMA (enthalpynmode_min_9Å) compromises the overall accuracy of MM/GBSA and MM/PBSA compared with the enthalpies calculated based on the minimized structures (enthalpymin). However, for the MD trajectories, the binding free energies can be improved by the inclusion of the conformation entropies predicted by either truncated-NMA under a relatively high dielectric constant (εin=4) or interaction entropy under εin=1~4. Although the inclusion of the truncated NMA based on the MD trajectories (ΔGnmode_md_9Å) under a relatively high dielectric constant give the overall best results and the lowest average absolute deviations against the experimental data (for ff03 force field), it needs too much computational time. Alternatively, considering that the interaction entropy does not need any additional computational cost and can give comparable (at high dielectric constant, εin=4) or even better (at low dielectric constant, εin=1~2) results than the truncated-NMA entropy (ΔGnmode_md_9Å), the interaction entropy approach is recommended to estimate the entropic component for MM/GBSA and MM/PBSA based on MD trajectories, especially for a diverse dataset. Furthermore, we compared the predictions of MM/GBSA with six different AMBER force fields. The results show that the ff03 force field (ff03 for proteins and gaff with AM1-BCC charges for ligands) performs the best, but the predictions given by the tested force fields are comparable, implying that the MM/GBSA predictions are not quite sensitive to force fields.

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Supplementary files

Publication details

The article was received on 12 Nov 2017, accepted on 01 May 2018 and first published on 02 May 2018


Article type: Paper
DOI: 10.1039/C7CP07623A
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Assessing the performance of MM/PBSA and MM/GBSA methods. 7. Entropy effects on the performance of end-point binding free energy calculation approaches

    H. Sun, L. Duan, F. Chen, H. Liu, Z. Wang, P. Pan, F. Zhu, J. Z. H. Zhang and T. Hou, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C7CP07623A

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