Retinal isomerization and water-pore formation in channelrhodopsin-2.
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| Title: | Retinal isomerization and water-pore formation in channelrhodopsin-2. |
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| Authors: | Ardevol, Albert1 albert.ardevol@biophys.mpg.de, Hummer, Gerhard1,2 gerhard.hummer@biophys.mpg.de |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 4/3/2018, Vol. 115 Issue 14, p3557-3562. 6p. |
| Subjects: | Ion channels, Isomerization, Molecular dynamics, Quantum mechanics, Quantum tunneling |
| Abstract: | Channelrhodopsin-2 (ChR2) is a light-sensitive ion channel widely used in optogenetics. Photoactivation triggers a trans-to-cis isomerization of a covalently bound retinal. Ensuing conformational changes open a cation-selective channel. We explore the structural dynamics in the early photocycle leading to channel opening by classical (MM) and quantum mechanical (QM) molecular simulations. With QM/MM simulations, we generated a protein-adapted force field for the retinal chromophore, which we validated against absorption spectra. In a 4-µs MM simulation of a dark-adapted ChR2 dimer, water entered the vestibules of the closed channel. Retinal all-trans to 13-cis isomerization, simulated with metadynamics, triggered a major restructuring of the charge cluster forming the channel gate. On a microsecond time scale, water penetrated the gate to form a membrane-spanning preopen pore between helices H1, H2, H3, and H7. This influx of water into an ion-impermeable preopen pore is consistent with time-resolved infrared spectroscopy and electrophysiology experiments. In the retinal 13-cis state, D253 emerged as the proton acceptor of the Schiff base. Upon proton transfer from the Schiff base to D253, modeled by QM/MM simulations, we obtained an early-M/P2 390-like intermediate. Rapid rotation of the unprotonated Schiff base toward the cytosolic side effectively prevents its reprotonation from the extracellular side. From MM and QM simulations, we gained detailed insight into the mechanism of ChR2 photoactivation and early events in pore formation. By rearranging the network of charges and hydrogen bonds forming the gate, water emerges as a key player in light-driven ChR2 channel opening. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 128909452 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Retinal isomerization and water-pore formation in channelrhodopsin-2. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Ardevol%2C+Albert%22">Ardevol, Albert</searchLink><relatesTo>1</relatesTo><i> albert.ardevol@biophys.mpg.de</i><br /><searchLink fieldCode="AR" term="%22Hummer%2C+Gerhard%22">Hummer, Gerhard</searchLink><relatesTo>1,2</relatesTo><i> gerhard.hummer@biophys.mpg.de</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 4/3/2018, Vol. 115 Issue 14, p3557-3562. 6p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Ion+channels%22">Ion channels</searchLink><br /><searchLink fieldCode="DE" term="%22Isomerization%22">Isomerization</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Quantum+mechanics%22">Quantum mechanics</searchLink><br /><searchLink fieldCode="DE" term="%22Quantum+tunneling%22">Quantum tunneling</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Channelrhodopsin-2 (ChR2) is a light-sensitive ion channel widely used in optogenetics. Photoactivation triggers a trans-to-cis isomerization of a covalently bound retinal. Ensuing conformational changes open a cation-selective channel. We explore the structural dynamics in the early photocycle leading to channel opening by classical (MM) and quantum mechanical (QM) molecular simulations. With QM/MM simulations, we generated a protein-adapted force field for the retinal chromophore, which we validated against absorption spectra. In a 4-µs MM simulation of a dark-adapted ChR2 dimer, water entered the vestibules of the closed channel. Retinal all-trans to 13-cis isomerization, simulated with metadynamics, triggered a major restructuring of the charge cluster forming the channel gate. On a microsecond time scale, water penetrated the gate to form a membrane-spanning preopen pore between helices H1, H2, H3, and H7. This influx of water into an ion-impermeable preopen pore is consistent with time-resolved infrared spectroscopy and electrophysiology experiments. In the retinal 13-cis state, D253 emerged as the proton acceptor of the Schiff base. Upon proton transfer from the Schiff base to D253, modeled by QM/MM simulations, we obtained an early-M/P2 390-like intermediate. Rapid rotation of the unprotonated Schiff base toward the cytosolic side effectively prevents its reprotonation from the extracellular side. From MM and QM simulations, we gained detailed insight into the mechanism of ChR2 photoactivation and early events in pore formation. By rearranging the network of charges and hydrogen bonds forming the gate, water emerges as a key player in light-driven ChR2 channel opening. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.1700091115 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 6 StartPage: 3557 Subjects: – SubjectFull: Ion channels Type: general – SubjectFull: Isomerization Type: general – SubjectFull: Molecular dynamics Type: general – SubjectFull: Quantum mechanics Type: general – SubjectFull: Quantum tunneling Type: general Titles: – TitleFull: Retinal isomerization and water-pore formation in channelrhodopsin-2. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Ardevol, Albert – PersonEntity: Name: NameFull: Hummer, Gerhard IsPartOfRelationships: – BibEntity: Dates: – D: 03 M: 04 Text: 4/3/2018 Type: published Y: 2018 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 115 – Type: issue Value: 14 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
| ResultId | 1 |
