Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.

Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Stefano Vanni, Marilisa Neri, Ivano Tavernelli, Ursula Rothlisberger
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2011
Materias:
Acceso en línea:https://doaj.org/article/793fc65429c64147b03e9fcb0b17908d
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:793fc65429c64147b03e9fcb0b17908d
record_format dspace
spelling oai:doaj.org-article:793fc65429c64147b03e9fcb0b17908d2021-11-18T05:50:47ZPredicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.1553-734X1553-735810.1371/journal.pcbi.1001053https://doaj.org/article/793fc65429c64147b03e9fcb0b17908d2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21253557/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β(1) and β(2) adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.Stefano VanniMarilisa NeriIvano TavernelliUrsula RothlisbergerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 1, p e1001053 (2011)
institution DOAJ
collection DOAJ
language EN
topic Biology (General)
QH301-705.5
spellingShingle Biology (General)
QH301-705.5
Stefano Vanni
Marilisa Neri
Ivano Tavernelli
Ursula Rothlisberger
Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
description Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β(1) and β(2) adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity.
format article
author Stefano Vanni
Marilisa Neri
Ivano Tavernelli
Ursula Rothlisberger
author_facet Stefano Vanni
Marilisa Neri
Ivano Tavernelli
Ursula Rothlisberger
author_sort Stefano Vanni
title Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
title_short Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
title_full Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
title_fullStr Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
title_full_unstemmed Predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
title_sort predicting novel binding modes of agonists to β adrenergic receptors using all-atom molecular dynamics simulations.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/793fc65429c64147b03e9fcb0b17908d
work_keys_str_mv AT stefanovanni predictingnovelbindingmodesofagoniststobadrenergicreceptorsusingallatommoleculardynamicssimulations
AT marilisaneri predictingnovelbindingmodesofagoniststobadrenergicreceptorsusingallatommoleculardynamicssimulations
AT ivanotavernelli predictingnovelbindingmodesofagoniststobadrenergicreceptorsusingallatommoleculardynamicssimulations
AT ursularothlisberger predictingnovelbindingmodesofagoniststobadrenergicreceptorsusingallatommoleculardynamicssimulations
_version_ 1718424795053293568