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Towards Ligand Docking Including Explicit Interface Water Molecules

Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms includi...

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Detalles Bibliográficos
Autores principales: Lemmon, Gordon, Meiler, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695863/
https://www.ncbi.nlm.nih.gov/pubmed/23840735
http://dx.doi.org/10.1371/journal.pone.0067536
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author Lemmon, Gordon
Meiler, Jens
author_facet Lemmon, Gordon
Meiler, Jens
author_sort Lemmon, Gordon
collection PubMed
description Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta’s ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9∶1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.
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spelling pubmed-36958632013-07-09 Towards Ligand Docking Including Explicit Interface Water Molecules Lemmon, Gordon Meiler, Jens PLoS One Research Article Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta’s ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9∶1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation. Public Library of Science 2013-06-28 /pmc/articles/PMC3695863/ /pubmed/23840735 http://dx.doi.org/10.1371/journal.pone.0067536 Text en © 2013 Lemmon, Meiler http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lemmon, Gordon
Meiler, Jens
Towards Ligand Docking Including Explicit Interface Water Molecules
title Towards Ligand Docking Including Explicit Interface Water Molecules
title_full Towards Ligand Docking Including Explicit Interface Water Molecules
title_fullStr Towards Ligand Docking Including Explicit Interface Water Molecules
title_full_unstemmed Towards Ligand Docking Including Explicit Interface Water Molecules
title_short Towards Ligand Docking Including Explicit Interface Water Molecules
title_sort towards ligand docking including explicit interface water molecules
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695863/
https://www.ncbi.nlm.nih.gov/pubmed/23840735
http://dx.doi.org/10.1371/journal.pone.0067536
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