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

• Verfasst von: Heinz, Leonard P. [VerfasserIn]
• Verfasst von: Kopec, Wojciech [VerfasserIn]
• Verfasst von: Groot, Bert L. de [VerfasserIn]
• Verfasst von: Fink, Rainer [VerfasserIn]
• Titel: In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways
• Verf.angabe: Leonard P. Heinz, Wojciech Kopec, Bert L. de Groot & Rainer H. A. Fink
• E-Jahr: 2018
• Jahr: 02 May 2018
• Umfang: 12 S.
• Fussnoten: Published: 02 May 2018 ; Gesehen am 27.08.2019
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Macmillan Publishers Limited, part of Springer Nature, 2011
• Jahr Quelle: 2018
• Band/Heft Quelle: 8(2018) article number: 6886 , 12 Seiten
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/s41598-018-25061-z
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1672174112

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