In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways

Abstract The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural...

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Autores principales:	Leonard P. Heinz, Wojciech Kopec, Bert L. de Groot, Rainer H. A. Fink
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dcef8c92b0e6429fb23a4aedce04b6ad
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spelling	oai:doaj.org-article:dcef8c92b0e6429fb23a4aedce04b6ad2021-12-02T11:40:36ZIn silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways10.1038/s41598-018-25061-z2045-2322https://doaj.org/article/dcef8c92b0e6429fb23a4aedce04b6ad2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25061-zhttps://doaj.org/toc/2045-2322Abstract The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural data, we performed molecular dynamics simulations on the entire ion channel as well as on a reduced model. We calculated potentials of mean force for Ba2+, Ca2+, Mg2+, K+, Na+ and Cl− ions using umbrella sampling to identify the key residues involved in ion permeation. We found two main binding sites for the cations, whereas the channel is strongly repulsive for chloride ions. Furthermore, the data is consistent with the model that the receptor achieves its ion selectivity by over-affinity for divalent cations in a calcium-block-like fashion. We reproduced the experimental conductance for potassium ions in permeation simulations with applied voltage. The analysis of the permeation paths shows that ions exit the pore via multiple pathways, which we suggest to be related to the experimental observation of different subconducting states.Leonard P. HeinzWojciech KopecBert L. de GrootRainer H. A. FinkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leonard P. Heinz Wojciech Kopec Bert L. de Groot Rainer H. A. Fink In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
description	Abstract The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural data, we performed molecular dynamics simulations on the entire ion channel as well as on a reduced model. We calculated potentials of mean force for Ba2+, Ca2+, Mg2+, K+, Na+ and Cl− ions using umbrella sampling to identify the key residues involved in ion permeation. We found two main binding sites for the cations, whereas the channel is strongly repulsive for chloride ions. Furthermore, the data is consistent with the model that the receptor achieves its ion selectivity by over-affinity for divalent cations in a calcium-block-like fashion. We reproduced the experimental conductance for potassium ions in permeation simulations with applied voltage. The analysis of the permeation paths shows that ions exit the pore via multiple pathways, which we suggest to be related to the experimental observation of different subconducting states.
format	article
author	Leonard P. Heinz Wojciech Kopec Bert L. de Groot Rainer H. A. Fink
author_facet	Leonard P. Heinz Wojciech Kopec Bert L. de Groot Rainer H. A. Fink
author_sort	Leonard P. Heinz
title	In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
title_short	In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
title_full	In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
title_fullStr	In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
title_full_unstemmed	In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
title_sort	in silico assessment of the conduction mechanism of the ryanodine receptor 1 reveals previously unknown exit pathways
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/dcef8c92b0e6429fb23a4aedce04b6ad
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_version_	1718395612424044544

In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways

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