Examining the Ensembles of Amyloid-ß Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method.
J Phys Chem B
; 126(1): 93-99, 2022 01 13.
Article
in En
| MEDLINE
| ID: mdl-34968059
ABSTRACT
The amyloid-ß (Aß) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aß-40 and Aß-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer's disease (AD). Experiments have shown that even though the natural abundance of Aß-42 is smaller than that for Aß-40, the Aß-42 is more aggregation-prone compared to Aß-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aß-40 and Aß-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alzheimer Disease
/
Intrinsically Disordered Proteins
Limits:
Humans
Language:
En
Journal:
J Phys Chem B
Journal subject:
QUIMICA
Year:
2022
Document type:
Article
Affiliation country:
Brazil