Thermodynamics calculation of protein-ligand interactions by QM/MM polarizable charge parameters

Journal of Biomolecular Structure & Dynamics
Jinan WangWeiliang Zhu

Abstract

The calculation of protein-ligand binding free energy (ΔG) is of great importance for virtual screening and drug design. Molecular dynamics (MD) simulation has been an attractive tool to investigate this scientific problem. However, the reliability of such approach is affected by many factors including electrostatic interaction calculation. Here, we present a practical protocol using quantum mechanics/molecular mechanics (QM/MM) calculations to generate polarizable QM protein charge (QMPC). The calculated QMPC of some atoms in binding pockets was obviously different from that calculated by AMBER ff03, which might significantly affect the calculated ΔG. To evaluate the effect, the MD simulations and MM/GBSA calculation with QMPC for 10 protein-ligand complexes, and the simulation results were then compared to those with the AMBER ff03 force field and experimental results. The correlation coefficient between the calculated ΔΔG using MM/GBSA under QMPC and the experimental data is .92, while that with AMBER ff03 force field is .47 for the complexes formed by streptavidin or its mutants and biotin. Moreover, the calculated ΔΔG with QMPC for the complexes formed by ERβ and five ligands is positively related to experimental result wi...Continue Reading

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Citations

Apr 15, 2016·Chemical Reviews·Ulf Ryde, Pär Söderhjelm
May 27, 2016·Journal of Biomolecular Structure & Dynamics·Yan QiaoJunbiao Chang
Jun 8, 2018·Chemical Biology & Drug Design·Jianzhong ChenWeiliang Zhu
Feb 23, 2020·Journal of Biomolecular Structure & Dynamics·S NehruS Arunachalam
May 1, 2018·Journal of Computational Chemistry·Yaqian WangXiao He
Apr 29, 2021·Chemistry : a European Journal·Anna LidskogKenneth Wärnmark

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Software Mentioned

GBSA
PB
Gaussian09
MM
AMBER
Delphi
RESP
nmode Amber
QMPFF
GAFF

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