Prediction of ligand binding mode among multiple cross-docking poses by molecular dynamics simulations
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Prediction of ligand binding mode among multiple cross-docking poses by molecular dynamics simulations Kai Liu1 · Hironori Kokubo2,3 Received: 20 December 2019 / Accepted: 21 August 2020 © Springer Nature Switzerland AG 2020
Abstract We propose a method to identify the correct binding mode of a ligand with a protein among multiple predicted docking poses. Our method consists of two steps. First, five independent MD simulations with different initial velocities are performed for each docking pose, in order to evaluate its stability. If the root-mean-square deviations (RMSDs) of heavy atoms from the docking pose are larger than a given threshold (2.0 Å) in all five parallel runs, the pose is filtered out and discarded. Then, we perform accurate all-atom binding free energy calculations for the residual poses only. The pose with the lowest binding free energy is identified as the correct pose. As a test case, we applied our method to a previously built cross-docking test set, which included 104 complex systems. We found that the present method could successfully identify the correct ligand binding mode for 72% (75/104) of the complexes for current test set. The possible reasons for the failure of the method in the other cases were investigated in detail, to enable future improvements. Keywords Docking pose discrimination · Molecular dynamics · Binding free energy calculation
Introduction The prediction of the binding mode of a ligand with a target protein is crucial for structure-based drug discovery. The binding mode can be experimentally obtained by X-ray diffraction, nuclear magnetic resonance (NMR) or cryo-electron microscopy [1, 2]. However, these experimental methods are often time-consuming and their practical application is limited to a small number of selected complex systems. Thus, great efforts have been made in developing theoretical calculations in this field, and docking calculations have Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00340-y) contains supplementary material, which is available to authorized users. * Hironori Kokubo kokubo.hironori06@chugai‑pharm.co.jp 1
Institute of Marine Drugs, Guangxi University of Chinese Medicine, No. 13, Wuhe Avenue, Nanning 530200, Guangxi, People’s Republic of China
2
Chemistry, Research Division, Axcelead Drug Discovery Partners, Inc, 26‑1, Muraoka‑Higashi 2‑chome, Fujisawa, Kanagawa 251‑8555, Japan
3
Present Address: Discovery Chemistry Department, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kanagawa, Japan
become a routine process for drug discovery [3–5]. Using molecular docking, it is relatively easy to identify the possible binding modes of new candidate molecules. In order to improve the performance of docking, various databases are publically established for the performance assessment and comparison of various docking programs, such as the PDBbind database, [6, 7] sc-PDB database, [8–10] the comparative assessment of scoring functions (CASF) benchmark, [11] the directory
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