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Predicting protein ligand binding motions with the conformation explorer

BACKGROUND: 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...

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Detalles Bibliográficos
Autores principales: Flores, Samuel C, Gerstein, Mark B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354956/
https://www.ncbi.nlm.nih.gov/pubmed/22032721
http://dx.doi.org/10.1186/1471-2105-12-417
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author Flores, Samuel C
Gerstein, Mark B
author_facet Flores, Samuel C
Gerstein, Mark B
author_sort Flores, Samuel C
collection PubMed
description BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: We demonstrate that the method in most cases successfully predicts the holo conformation given only an apo structure.
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spelling pubmed-33549562012-05-18 Predicting protein ligand binding motions with the conformation explorer Flores, Samuel C Gerstein, Mark B BMC Bioinformatics Methodology Article BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: We demonstrate that the method in most cases successfully predicts the holo conformation given only an apo structure. BioMed Central 2011-10-27 /pmc/articles/PMC3354956/ /pubmed/22032721 http://dx.doi.org/10.1186/1471-2105-12-417 Text en Copyright ©2011 Flores and Gerstein; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Methodology Article
Flores, Samuel C
Gerstein, Mark B
Predicting protein ligand binding motions with the conformation explorer
title Predicting protein ligand binding motions with the conformation explorer
title_full Predicting protein ligand binding motions with the conformation explorer
title_fullStr Predicting protein ligand binding motions with the conformation explorer
title_full_unstemmed Predicting protein ligand binding motions with the conformation explorer
title_short Predicting protein ligand binding motions with the conformation explorer
title_sort predicting protein ligand binding motions with the conformation explorer
topic Methodology Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354956/
https://www.ncbi.nlm.nih.gov/pubmed/22032721
http://dx.doi.org/10.1186/1471-2105-12-417
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