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Open Access Highly Accessed Methodology article

Predicting protein ligand binding motions with the conformation explorer

Samuel C Flores1* and Mark B Gerstein23

Author Affiliations

1 Department of Cell and Molecular Biology, Uppsala University, BMC Box 596, Uppsala, 75124, Sweden

2 Department of Molecular Biophysics and Biochemistry, Yale University, PO Box 208114 MBB, New Haven, CT, 06520, USA

3 Department of Computer Science, Yale University, PO Box 208114 MBB, New Haven, CT, 06520, USA

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BMC Bioinformatics 2011, 12:417  doi:10.1186/1471-2105-12-417

Published: 27 October 2011



Knowledge of the structure of proteins bound to known or potential ligands is crucial for biological understanding and drug design. Often the 3D structure of the protein is available in some conformation, but binding the ligand of interest may involve a large scale conformational change which is difficult to predict with existing methods.


We describe how to generate ligand binding conformations of proteins that move by hinge bending, the largest class of motions. First, we predict the location of the hinge between domains. Second, we apply an Euler rotation to one of the domains about the hinge point. Third, we compute a short-time dynamical trajectory using Molecular Dynamics to equilibrate the protein and ligand and correct unnatural atomic positions. Fourth, we score the generated structures using a novel fitness function which favors closed or holo structures. By iterating the second through fourth steps we systematically minimize the fitness function, thus predicting the conformational change required for small ligand binding for five well studied proteins.


We demonstrate that the method in most cases successfully predicts the holo conformation given only an apo structure.