Effects of Familial Alzheimer's Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide

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dc.contributor.authorDavidson, Darcy S.en
dc.contributor.authorKraus, Joshua A.en
dc.contributor.authorMontgomery, Julia M.en
dc.contributor.authorLemkul, Justin A.en
dc.date.accessioned2023-01-12T19:08:00Zen
dc.date.available2023-01-12T19:08:00Zen
dc.date.issued2022-10-06en
dc.date.updated2023-01-12T18:40:40Zen
dc.description.abstractFamilial Alzheimer's disease (FAD) mutations of the amyloid β-peptide (Aβ) are known to lead to early onset and more aggressive Alzheimer's disease. FAD mutations such as "Iowa" (D23N), "Arctic" (E22G), "Italian" (E22K), and "Dutch" (E22Q) have been shown to accelerate Aβ aggregation relative to the wild-type (WT). The mechanism by which these mutations facilitate increased aggregation is unknown, but each mutation results in a change in the net charge of the peptide. Previous studies have used nonpolarizable force fields to study Aβ, providing some insight into how this protein unfolds. However, nonpolarizable force fields have fixed charges that lack the ability to redistribute in response to changes in local electric fields. Here, we performed polarizable molecular dynamics simulations on the full-length Aβ42of WT and FAD mutations and calculated folding free energies of the Aβ15-27fragment via umbrella sampling. By studying both the full-length Aβ42and a fragment containing mutations and the central hydrophobic cluster (residues 17-21), we were able to systematically study how these FAD mutations impact secondary and tertiary structure and the thermodynamics of folding. Electrostatic interactions, including those between permanent and induced dipoles, affected side-chain properties, salt bridges, and solvent interactions. The FAD mutations resulted in shifts in the electronic structure and solvent accessibility at the central hydrophobic cluster and the hydrophobic C-terminal region. Using umbrella sampling, we found that the folding of the WT and E22 mutants is enthalpically driven, whereas the D23N mutant is entropically driven, arising from a different unfolding pathway and peptide-bond dipole response. Together, the unbiased, full-length, and umbrella sampling simulations of fragments reveal that the FAD mutations perturb nearby residues and others in hydrophobic regions to potentially alter solubility. These results highlight the role electronic polarizability plays in amyloid misfolding and the role of heterogeneous microenvironments that arise as conformational change takes place.en
dc.description.versionAccepted versionen
dc.format.extentPages 7552-7566en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1021/acs.jpcb.2c03520en
dc.identifier.eissn1520-5207en
dc.identifier.issn1520-6106en
dc.identifier.issue39en
dc.identifier.orcidLemkul, Justin [0000-0001-6661-8653]en
dc.identifier.pmid36150020en
dc.identifier.urihttp://hdl.handle.net/10919/113149en
dc.identifier.volume126en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36150020en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectAlzheimer's Diseaseen
dc.subjectAlzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)en
dc.subjectAcquired Cognitive Impairmenten
dc.subjectNeurosciencesen
dc.subjectDementiaen
dc.subjectBrain Disordersen
dc.subjectAgingen
dc.subjectNeurodegenerativeen
dc.subject2 Aetiologyen
dc.subject2.1 Biological and endogenous factorsen
dc.subject.meshHumansen
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshFlavin-Adenine Dinucleotideen
dc.subject.meshPeptide Fragmentsen
dc.subject.meshSolventsen
dc.subject.meshProtein Foldingen
dc.subject.meshMutationen
dc.subject.meshAmyloid beta-Peptidesen
dc.titleEffects of Familial Alzheimer's Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptideen
dc.title.serialJournal of Physical Chemistry Ben
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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