Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.

A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations. The transducin G38D mutant a...

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Autores principales:	Simona Mariani, Daniele Dell'Orco, Angelo Felline, Francesco Raimondi, Francesca Fanelli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ce095354a1904a2a86f3cd3268a5d9d2
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spelling	oai:doaj.org-article:ce095354a1904a2a86f3cd3268a5d9d22021-11-18T05:53:38ZNetwork and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.1553-734X1553-735810.1371/journal.pcbi.1003207https://doaj.org/article/ce095354a1904a2a86f3cd3268a5d9d22013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24009494/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations. The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect. Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.Simona MarianiDaniele Dell'OrcoAngelo FellineFrancesco RaimondiFrancesca FanelliPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 8, p e1003207 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Simona Mariani Daniele Dell'Orco Angelo Felline Francesco Raimondi Francesca Fanelli Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
description	A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations. The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect. Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.
format	article
author	Simona Mariani Daniele Dell'Orco Angelo Felline Francesco Raimondi Francesca Fanelli
author_facet	Simona Mariani Daniele Dell'Orco Angelo Felline Francesco Raimondi Francesca Fanelli
author_sort	Simona Mariani
title	Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
title_short	Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
title_full	Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
title_fullStr	Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
title_full_unstemmed	Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
title_sort	network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ce095354a1904a2a86f3cd3268a5d9d2
work_keys_str_mv	AT simonamariani networkandatomisticsimulationsunveilthestructuraldeterminantsofmutationslinkedtoretinaldiseases AT danieledellorco networkandatomisticsimulationsunveilthestructuraldeterminantsofmutationslinkedtoretinaldiseases AT angelofelline networkandatomisticsimulationsunveilthestructuraldeterminantsofmutationslinkedtoretinaldiseases AT francescoraimondi networkandatomisticsimulationsunveilthestructuraldeterminantsofmutationslinkedtoretinaldiseases AT francescafanelli networkandatomisticsimulationsunveilthestructuraldeterminantsofmutationslinkedtoretinaldiseases
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Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.

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