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Effect of Familial Mutations on the Interconversion of alpha-Helix to beta-Sheet Structures in an Amyloid-Forming Peptide: Insight from Umbrella Sampling Simulations
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-3173-5993
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China..ORCID iD: 0000-0002-1763-9383
2019 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 3, p. 1347-1354Article in journal (Refereed) Published
Abstract [en]

Understanding the initial events of aggregation of amyloid beta monomers to form beta-sheet rich fibrils is useful for the development of therapeutics for Alzheimer's disease. In this context, the changes in energetics involved in the aggregation of helical amyloid beta monomers into beta-sheet rich dimers have been investigated using umbrella sampling simulations and density functional theory calculations. The results from umbrella sampling simulations for the free energy profile for the interconversion closely agree with the results of density functional theory calculations. The results reveal that helical peptides converted to beta-sheet structures through coil-like conformations as intermediates that are mostly stabilized by intramolecular hydrogen bonds. The stabilization of intermediate structures could be a possible way to inhibit fibril formation. Mutations substantially decrease the height of the energy barrier for interconversion from alpha-helix to beta-sheet structure when compared to that of the wild type, something that is attributed to an increase in the number of intramolecular hydrogen bonds between backbone atoms in the coil structures that correspond to a maximum value on the free energy surface. The reduction of the energy barrier leads to an enhancement of the rate of aggregation of amyloid beta monomers upon introduction of various familial mutations, which is consistent with previous experimental reports.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019. Vol. 10, no 3, p. 1347-1354
Keywords [en]
Amyloid forming peptide, mutation effect on rate of aggregation, Alzheimer's disease, free energy for alpha-helix to beta-sheet interconversion, umbrella sampling simulations, familial mutations
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-249894DOI: 10.1021/acschemneuro.8b00425ISI: 000462259900041PubMedID: 30586502Scopus ID: 2-s2.0-85063224636OAI: oai:DiVA.org:kth-249894DiVA, id: diva2:1307324
Note

QC 20190426

Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-04-26Bibliographically approved

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