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A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.

cam.issuedOnline2022-06
dc.contributor.authorLöhr, Thomas
dc.contributor.authorKohlhoff, Kai
dc.contributor.authorHeller, Gabriella T
dc.contributor.authorCamilloni, Carlo
dc.contributor.authorVendruscolo, Michele
dc.contributor.orcidCamilloni, Carlo [0000-0002-9923-8590]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.date.accessioned2022-07-03T01:02:15Z
dc.date.available2022-07-03T01:02:15Z
dc.date.issued2022-06-15
dc.date.updated2022-07-03T01:02:15Z
dc.description.abstractThe 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.doi10.17863/CAM.86125
dc.identifier.eissn1948-7193
dc.identifier.issn1948-7193
dc.identifier.otherPMC9204762
dc.identifier.other35649268
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338712
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/acschemneuro.2c00116
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1948-7193
dc.sourcenlmid: 101525337
dc.subjectAlzheimer’s disease
dc.subjectAβ42 peptide
dc.subjectnative state
dc.subjectsmall molecule
dc.subjectAlzheimer Disease
dc.subjectAmyloid beta-Peptides
dc.subjectEntropy
dc.subjectHumans
dc.subjectIntrinsically Disordered Proteins
dc.subjectPeptide Fragments
dc.titleA Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide.
dc.typeArticle
dcterms.dateAccepted2022-05-04
prism.endingPage1745
prism.issueIdentifier12
prism.publicationNameACS Chem Neurosci
prism.startingPage1738
prism.volume13
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acschemneuro.2c00116

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