Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.

Site-directed mutagenesis combined with binding affinity measurements is widely used to probe the nature of ligand interactions with GPCRs. Such experiments, as well as structure-activity relationships for series of ligands, are usually interpreted with computationally derived models of ligand bindi...

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Autores principales:	Lars Boukharta, Hugo Gutiérrez-de-Terán, Johan Aqvist
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ad9c8b7c7b9a4a5eb841bf423e044df6
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spelling	oai:doaj.org-article:ad9c8b7c7b9a4a5eb841bf423e044df62021-11-18T05:52:57ZComputational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.1553-734X1553-735810.1371/journal.pcbi.1003585https://doaj.org/article/ad9c8b7c7b9a4a5eb841bf423e044df62014-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24743773/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Site-directed mutagenesis combined with binding affinity measurements is widely used to probe the nature of ligand interactions with GPCRs. Such experiments, as well as structure-activity relationships for series of ligands, are usually interpreted with computationally derived models of ligand binding modes. However, systematic approaches for accurate calculations of the corresponding binding free energies are still lacking. Here, we report a computational strategy to quantitatively predict the effects of alanine scanning and ligand modifications based on molecular dynamics free energy simulations. A smooth stepwise scheme for free energy perturbation calculations is derived and applied to a series of thirteen alanine mutations of the human neuropeptide Y1 receptor and series of eight analogous antagonists. The robustness and accuracy of the method enables univocal interpretation of existing mutagenesis and binding data. We show how these calculations can be used to validate structural models and demonstrate their ability to discriminate against suboptimal ones.Lars BoukhartaHugo Gutiérrez-de-TeránJohan AqvistPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 4, p e1003585 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Lars Boukharta Hugo Gutiérrez-de-Terán Johan Aqvist Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
description	Site-directed mutagenesis combined with binding affinity measurements is widely used to probe the nature of ligand interactions with GPCRs. Such experiments, as well as structure-activity relationships for series of ligands, are usually interpreted with computationally derived models of ligand binding modes. However, systematic approaches for accurate calculations of the corresponding binding free energies are still lacking. Here, we report a computational strategy to quantitatively predict the effects of alanine scanning and ligand modifications based on molecular dynamics free energy simulations. A smooth stepwise scheme for free energy perturbation calculations is derived and applied to a series of thirteen alanine mutations of the human neuropeptide Y1 receptor and series of eight analogous antagonists. The robustness and accuracy of the method enables univocal interpretation of existing mutagenesis and binding data. We show how these calculations can be used to validate structural models and demonstrate their ability to discriminate against suboptimal ones.
format	article
author	Lars Boukharta Hugo Gutiérrez-de-Terán Johan Aqvist
author_facet	Lars Boukharta Hugo Gutiérrez-de-Terán Johan Aqvist
author_sort	Lars Boukharta
title	Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
title_short	Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
title_full	Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
title_fullStr	Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
title_full_unstemmed	Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.
title_sort	computational prediction of alanine scanning and ligand binding energetics in g-protein coupled receptors.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ad9c8b7c7b9a4a5eb841bf423e044df6
work_keys_str_mv	AT larsboukharta computationalpredictionofalaninescanningandligandbindingenergeticsingproteincoupledreceptors AT hugogutierrezdeteran computationalpredictionofalaninescanningandligandbindingenergeticsingproteincoupledreceptors AT johanaqvist computationalpredictionofalaninescanningandligandbindingenergeticsingproteincoupledreceptors
_version_	1718424686812987392

Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors.

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