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

The amyloid-{beta} (A{beta}) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to A{beta}40 and A{beta}42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimers disease (AD). Experiments have shown that even though the natural abundance of A{beta}42 is smaller than that for A{beta}40, the A{beta}42 is more aggregation-prone compared to A{beta}40. Moreover, several single-point mutations are associated with early-onset forms of AD. This work analyzes coarse-grained AWSEM simulations of normal A{beta}40 and A{beta}42 monomers, along with six single-point mutations associated with early on set 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.