Journal article
Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid β-Protein
Biomolecules (Basel, Switzerland), v 14(7), p774
28 Jun 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer’s disease (AD) is a neurological disorder associated with amyloid β-protein (Aβ) assembly into toxic oligomers. In addition to the two predominant alloforms, Aβ1−40 and Aβ1−42, other C-terminally truncated Aβ peptides, including Aβ1−38 and Aβ1−43, are produced in the brain. Here, we use discrete molecular dynamics (DMD) and a four-bead protein model with amino acid-specific hydropathic interactions, DMD4B-HYDRA, to examine oligomer formation of Aβ1−38, Aβ1−40, Aβ1−42, and Aβ1−43. Self-assembly of 32 unstructured monomer peptides into oligomers is examined using 32 replica DMD trajectories for each of the four peptides. In a quasi-steady state, Aβ1−38 and Aβ1−40 adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas Aβ1−42 and Aβ1−43 oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for Aβ1−42) or octamers and pentadecamers (for Aβ1−43). The free energy landscapes reveal isoform- and oligomer-order specific structural and morphological features of oligomer ensembles. Our results show that oligomers of each of the four isoforms have unique features, with Aβ1−42 alone resulting in oligomers with disordered and solvent-exposed N-termini. Our findings help unravel the structure–function paradigm governing oligomers formed by various Aβ isoforms.
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Details
- Title
- Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid β-Protein
- Creators
- Rachit PandeyBrigita Urbanc - Drexel University
- Publication Details
- Biomolecules (Basel, Switzerland), v 14(7), p774
- Publisher
- MDPI; BASEL
- Number of pages
- 21
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:001278196500001
- Scopus ID
- 2-s2.0-85199643427
- Other Identifier
- 991021892014204721
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- Web of Science research areas
- Biochemistry & Molecular Biology