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Flipdock: Docking flexible ligands into flexible receptors

Academic Article
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Overview

authors

  • Zhao, Y.
  • Sanner, Michel

publication date

  • August 2007

journal

  • Proteins-Structure Function and Bioinformatics  Journal

abstract

  • Conformational changes of biological macromolecules when binding with ligands have long been observed and remain a challenge for automated docking methods. Here we present a novel protein-ligand docking software called FLIPDock (Flexible LIgand-Protein Docking) allowing the automated docking of flexible ligand molecules into active sites of flexible receptor molecules. In FLIPDock, conformational spaces of molecules are encoded using a data structure that we have developed recently called the Flexibility Tree (FT). While the FT can represent fully flexible ligands, it was initially designed as a hierarchical and multiresolution data structure for the selective encoding of conformational subspaces of large biological macromolecules. These conformational subspaces can be built to span a range of conformations important for the biological activity of a protein. A variety of motions can be combined, ranging from domains moving as rigid bodies or backbone atoms undergoing normal mode-based deformations, to side chains assuming rotameric conformations. In addition, these conformational subspaces are parameterized by a small number of variables which can be searched during the docking process, thus effectively modeling the conformational changes in a flexible receptor. FLIPDock searches the variables using genetic algorithm-based search techniques and evaluates putative docking complexes with a scoring function based on the AutoDock3.05 force-field. In this paper, we describe the concepts behind FLIPDock and the overall architecture of the program. We demonstrate FLIPDock's ability to solve docking problems in which the assumption of a rigid receptor previously prevented the successful docking of known ligands. In particular, we repeat an earlier cross docking experiment and demonstrate an increased success rate of 93.5%, compared to original 72% success rate achieved by AutoDock over the 400 cross-docking calculations. We also demonstrate FLIPDock's ability to handle conformational changes involving backbone motion by docking balanol to an adenosine-binding pocket of protein kinase A.

subject areas

  • Ligands
  • Protein Conformation
  • Receptors, Cell Surface
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Research

keywords

  • HIV-1 protease
  • docking
  • induced fit
  • protein flexibility
  • protein kinase A
  • rotamer library
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Identity

International Standard Serial Number (ISSN)

  • 0887-3585

Digital Object Identifier (DOI)

  • 10.1002/prot.21423

PubMed ID

  • 17523154
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Additional Document Info

start page

  • 726

end page

  • 737

volume

  • 68

issue

  • 3

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