Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
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| Title: | Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. |
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| Authors: | Musgaard, Maria1 maria.musgaard@bioch.ox.ac.uk, Biggin, Philip C.1 philip.biggin@bioch.ox.ac.uk |
| Source: | Journal of Chemical Information & Modeling. Sep2016, Vol. 56 Issue 9, p1787-1797. 11p. |
| Subjects: | Molecular dynamics, Ligand binding (Biochemistry), Protein-protein interactions, Glutamate receptors, Protein conformation |
| Abstract: | The stability of protein-protein interfaces can be essential for protein function. For ionotropic glutamate receptors, a family of ligand-gated ion channels vital for normal function of the central nervous system, such an interface exists between the extracellular ligand binding domains (LBDs). In the full-length protein, the LBDs are arranged as a dimer of dimers. Agonist binding to the LBDs opens the ion channel, and briefly after activation the receptor desensitizes. Several residues at the LBD dimer interface are known to modulate desensitization, and conformational changes around these residues are believed to be involved in the state transition. The general hypothesis is that the interface is disrupted upon desensitization, and structural evidence suggests that the disruption might be substantial. However, when cross-linking the central part of this interface, functional data suggest that the receptor can still undergo desensitization, contradicting the hypothesis of major interface disruption. Here, we illustrate how opening the dimer interface using steered molecular dynamics (SMD) simulations, and analyzing the work values required, provides a quantitative measure for interface stability. For one subtype of glutamate receptors, which is regulated by ion binding to the dimer interface, we show that opening the interface without ions bound requires less work than with ions present, suggesting that ion binding indeed stabilizes the interface. Likewise, for interface mutants with longer-lived active states, the interface is more stable, while the work required to open the interface is reduced for less active mutants. Moreover, a cross-linked mutant can still undergo initial interface opening motions similar to the native receptor and at similar energetic cost. Thus, our results support that interface opening is involved in desensitization. Furthermore, they provide reconciliation of apparently opposing data and demonstrate that SMD simulations can give relevant biological insight into longer time scale processes without the need for expensive calculations. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society 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 |
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| Header | DbId: egs DbLabel: Engineering Source An: 118508263 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Musgaard%2C+Maria%22">Musgaard, Maria</searchLink><relatesTo>1</relatesTo><i> maria.musgaard@bioch.ox.ac.uk</i><br /><searchLink fieldCode="AR" term="%22Biggin%2C+Philip+C%2E%22">Biggin, Philip C.</searchLink><relatesTo>1</relatesTo><i> philip.biggin@bioch.ox.ac.uk</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+Chemical+Information+%26+Modeling%22">Journal of Chemical Information & Modeling</searchLink>. Sep2016, Vol. 56 Issue 9, p1787-1797. 11p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29%22">Ligand binding (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Protein-protein+interactions%22">Protein-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Glutamate+receptors%22">Glutamate receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+conformation%22">Protein conformation</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: The stability of protein-protein interfaces can be essential for protein function. For ionotropic glutamate receptors, a family of ligand-gated ion channels vital for normal function of the central nervous system, such an interface exists between the extracellular ligand binding domains (LBDs). In the full-length protein, the LBDs are arranged as a dimer of dimers. Agonist binding to the LBDs opens the ion channel, and briefly after activation the receptor desensitizes. Several residues at the LBD dimer interface are known to modulate desensitization, and conformational changes around these residues are believed to be involved in the state transition. The general hypothesis is that the interface is disrupted upon desensitization, and structural evidence suggests that the disruption might be substantial. However, when cross-linking the central part of this interface, functional data suggest that the receptor can still undergo desensitization, contradicting the hypothesis of major interface disruption. Here, we illustrate how opening the dimer interface using steered molecular dynamics (SMD) simulations, and analyzing the work values required, provides a quantitative measure for interface stability. For one subtype of glutamate receptors, which is regulated by ion binding to the dimer interface, we show that opening the interface without ions bound requires less work than with ions present, suggesting that ion binding indeed stabilizes the interface. Likewise, for interface mutants with longer-lived active states, the interface is more stable, while the work required to open the interface is reduced for less active mutants. Moreover, a cross-linked mutant can still undergo initial interface opening motions similar to the native receptor and at similar energetic cost. Thus, our results support that interface opening is involved in desensitization. Furthermore, they provide reconciliation of apparently opposing data and demonstrate that SMD simulations can give relevant biological insight into longer time scale processes without the need for expensive calculations. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of Chemical Information & Modeling is the property of American Chemical Society 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: 10.1021/acs.jcim.6b00297 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 11 StartPage: 1787 Subjects: – SubjectFull: Molecular dynamics Type: general – SubjectFull: Ligand binding (Biochemistry) Type: general – SubjectFull: Protein-protein interactions Type: general – SubjectFull: Glutamate receptors Type: general – SubjectFull: Protein conformation Type: general Titles: – TitleFull: Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Musgaard, Maria – PersonEntity: Name: NameFull: Biggin, Philip C. IsPartOfRelationships: – BibEntity: Dates: – D: 26 M: 09 Text: Sep2016 Type: published Y: 2016 Identifiers: – Type: issn-print Value: 15499596 Numbering: – Type: volume Value: 56 – Type: issue Value: 9 Titles: – TitleFull: Journal of Chemical Information & Modeling Type: main |
| ResultId | 1 |
