Pyroglutamylation modulates electronic properties and the conformational ensemble of the amyloid β-peptide

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dc.contributor.authorDavidson, Darcy S.en
dc.contributor.authorLemkul, Justin A.en
dc.date.accessioned2025-01-08T18:36:52Zen
dc.date.available2025-01-08T18:36:52Zen
dc.date.issued2024-03-04en
dc.description.abstractAlzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid-β (Aβ) plaques. The underlying cause of AD is unknown, however, post-translational modifications (PTMs) of Aβ have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in Aβ, Glu3 and Glu11. This modification of Aβ involves the truncation and charge-neutralization of N-terminal glutamate, causing Aβ to become more hydrophobic and prone to aggregation. The molecular mechanism by which the introduction of pyroglutamate (pE) promotes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and truncation of the N-terminus plays on Aβ conformational sampling, we used the Drude polarizable force field (FF) to perform molecular dynamics simulations on AβpE3–42 and AβpE11–42 and comparing their properties to previous simulations of Aβ1–42. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore providing novel insights into the role that charge plays in protein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamylation on Aβ. We found that AβpE3–42 and AβpE11–42 alter the permanent and induced dipoles of the peptide. Specifically, we found that AβpE3–42 and AβpE11–42 have modification-specific backbone and sidechain polarization response and perturbed solvation properties that shift the Aβ conformational ensemble.en
dc.description.versionAccepted versionen
dc.format.extentPages 842-853en
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1002/prot.26677en
dc.identifier.eissn1097-0134en
dc.identifier.issn0887-3585en
dc.identifier.issue7en
dc.identifier.orcidLemkul, Justin [0000-0001-6661-8653]en
dc.identifier.pmid38436541en
dc.identifier.urihttps://hdl.handle.net/10919/123964en
dc.identifier.volume92en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/38436541en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAlzheimer's diseaseen
dc.subjectamyloid-betaen
dc.subjectDrude oscillatoren
dc.subjectpolarizable molecular dynamics simulationsen
dc.subjectpost-translational modificationsen
dc.subjectpyroglutamateen
dc.subjectamyloid‐βen
dc.subjectpost‐translational modificationsen
dc.subject.meshHumansen
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshPyrrolidonecarboxylic Aciden
dc.subject.meshPeptide Fragmentsen
dc.subject.meshProtein Processing, Post-Translationalen
dc.subject.meshProtein Conformationen
dc.subject.meshStatic Electricityen
dc.subject.meshMolecular Dynamics Simulationen
dc.subject.meshAmyloid beta-Peptidesen
dc.subject.meshHydrophobic and Hydrophilic Interactionsen
dc.titlePyroglutamylation modulates electronic properties and the conformational ensemble of the amyloid β-peptideen
dc.title.serialProteins-Structure Function and Bioinformaticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2024-02-08en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciencesen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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