EXPLORING THE ENERGY LANDSCAPES OF AMYLOID-β AGGREGATES

A significant portion of the proteome in all domains of life comprises proteins that lack a stable structure, which are known as intrinsically disordered proteins (IDPs). Their disordered nature and correspondingly large structural fluctuations lead to a complex high-dimensional structural phase-space. Because of the lack of a reference conformation, their energy landscape representation is a significant challenge. Due to their extreme malleability, IDPs are susceptible to multiple protein interactions, and their dysfunctions are associated with numerous pathologies. In this presentation, we investigate amyloid-β (Aβ) monomers and aggregates. Aβs are produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-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 Aβ-42 is smaller than that for Aβ-40, Aβ-42 is more aggregation-prone compared to Aβ-40. We analyze Aβ atomistic trajectories of an ensemble of interacting monomers simulated using AWSEM forcefield. Their energy landscapes were elucidated using the energy landscape visualization method (ELViM),1 a reaction-coordinate-free approach suited to explore frustrated energy landscapes. ELViM is shown to distinguish the monomer ensembles of isoforms that rapidly form fibers from those that do not form fibers as readily. The results shed light on the initial aggregation mechanism associated with proto-fiber formation.
[1] A.B. Oliveira Jr. et al, J. Chem. Theory Comput., 15, 6482-6490 (2019).