Examining the Ensembles of Amyloid-beta Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method

MN Sanches and K Knapp and AB Oliveira and PG Wolynes and JN Onuchic and VBP Leite, JOURNAL OF PHYSICAL CHEMISTRY B (2021).

DOI: 10.1021/acs.jpcb.1c08525

The amyloid-fl (Afl) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Afl-40 and Afl-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 Afl-42 is smaller than that for Afl-40, the Afl-42 is more aggregation-prone compared to Afl-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 Afl-40 and Afl-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 reactioncoordinate-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.

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