Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins

Abstract Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasonin...

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Autores principales:	Letícia Stock, Juliana Hosoume, Werner Treptow
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f5a6d56a3af4689b1df525391c8295e
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spelling	oai:doaj.org-article:4f5a6d56a3af4689b1df525391c8295e2021-12-02T11:40:57ZConcentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins10.1038/s41598-017-05896-82045-2322https://doaj.org/article/4f5a6d56a3af4689b1df525391c8295e2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05896-8https://doaj.org/toc/2045-2322Abstract Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein-ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available.Letícia StockJuliana HosoumeWerner TreptowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Letícia Stock Juliana Hosoume Werner Treptow Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
description	Abstract Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein-ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available.
format	article
author	Letícia Stock Juliana Hosoume Werner Treptow
author_facet	Letícia Stock Juliana Hosoume Werner Treptow
author_sort	Letícia Stock
title	Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
title_short	Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
title_full	Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
title_fullStr	Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
title_full_unstemmed	Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins
title_sort	concentration-dependent binding of small ligands to multiple saturable sites in membrane proteins
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4f5a6d56a3af4689b1df525391c8295e
work_keys_str_mv	AT leticiastock concentrationdependentbindingofsmallligandstomultiplesaturablesitesinmembraneproteins AT julianahosoume concentrationdependentbindingofsmallligandstomultiplesaturablesitesinmembraneproteins AT wernertreptow concentrationdependentbindingofsmallligandstomultiplesaturablesitesinmembraneproteins
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Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins

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