A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.
cam.issuedOnline | 2022-06 | |
dc.contributor.author | Löhr, Thomas | |
dc.contributor.author | Kohlhoff, Kai | |
dc.contributor.author | Heller, Gabriella T | |
dc.contributor.author | Camilloni, Carlo | |
dc.contributor.author | Vendruscolo, Michele | |
dc.contributor.orcid | Camilloni, Carlo [0000-0002-9923-8590] | |
dc.contributor.orcid | Vendruscolo, Michele [0000-0002-3616-1610] | |
dc.date.accessioned | 2022-07-03T01:02:15Z | |
dc.date.available | 2022-07-03T01:02:15Z | |
dc.date.issued | 2022-06-15 | |
dc.date.updated | 2022-07-03T01:02:15Z | |
dc.description.abstract | The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins. | |
dc.identifier.doi | 10.17863/CAM.86125 | |
dc.identifier.eissn | 1948-7193 | |
dc.identifier.issn | 1948-7193 | |
dc.identifier.other | PMC9204762 | |
dc.identifier.other | 35649268 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/338712 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | American Chemical Society (ACS) | |
dc.publisher.url | http://dx.doi.org/10.1021/acschemneuro.2c00116 | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | essn: 1948-7193 | |
dc.source | nlmid: 101525337 | |
dc.subject | Alzheimer’s disease | |
dc.subject | Aβ42 peptide | |
dc.subject | native state | |
dc.subject | small molecule | |
dc.subject | Alzheimer Disease | |
dc.subject | Amyloid beta-Peptides | |
dc.subject | Entropy | |
dc.subject | Humans | |
dc.subject | Intrinsically Disordered Proteins | |
dc.subject | Peptide Fragments | |
dc.title | A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide. | |
dc.type | Article | |
dcterms.dateAccepted | 2022-05-04 | |
prism.endingPage | 1745 | |
prism.issueIdentifier | 12 | |
prism.publicationName | ACS Chem Neurosci | |
prism.startingPage | 1738 | |
prism.volume | 13 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0/ | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1021/acschemneuro.2c00116 |
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