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Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand

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Abstract

Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, based on the RosettaLigand protocol. This approach incorporates the flexibility of interfacial water molecules and modeling of the interface of the receptor into the original RosettaLigand. In a coarse sampling step, SWRosettaLigand pre-optimizes the initial position of the water molecules, docks the ligand to the receptor with explicit water molecules, and minimizes the predicted structure with water molecules. The receptor backbone interface is treated as a loop and perturbed and refined by kinematic closure, or cyclic coordinate descent algorithm, with the presence of the ligand. In two cross-docking test sets, it was identified that for 8 out of 14, and 16 out of 22, test instances, the top-ranked structures by SWRosettaLigand achieved better accuracy than other protocols.

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Acknowledgments

The authors thank the Rosetta developers for their great help. Thanks to Wei Yang for his help in carrying out MD simulations. Supported by the National Science Foundation of China under the grant number 61170125.

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Authors and Affiliations

  1. School of Computer Science and Technology, Soochow University, P.O.Box 158, 1 Shizi Street, Suzhou, Jiangsu, 215006, China

    Linqing Li & Qiang Lü

  2. Wujiang Rural Commercial Bank, Suzhou, Jiangsu, 215006, China

    Weiwei Xu

  3. Jiangsu Provincial Key Lab for Information Processing Technologies, Suzhou, China

    Qiang Lü

Authors
  1. Linqing Li
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  2. Weiwei Xu
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Correspondence to Qiang Lü.

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Li, L., Xu, W. & Lü, Q. Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand. J Mol Model 21, 294 (2015). https://doi.org/10.1007/s00894-015-2834-7

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