Amyloid-β (Aβ) aggregation into toxic oligomers and fibrils is a hallmark of Alzheimer's disease. The Aβ16-22 fragment plays a critical role in the early stages of the aggregation of full-length Aβ peptides. Aggregation of Aβ16-22 is primarily driven by hydrophobic interactions within the LVFF core and electrostatic attraction between flanking residues K16 (+) and E22 (-). To dissect the relative contributions of these forces, we introduced a K16F/E22F double mutation, which eliminates charged residues while enhancing hydrophobicity and aromaticity. This substitution provides a controlled system to evaluate how specific interactions influence aggregation behavior. Using a novel computational protocol, featuring a strategically designed 4-mer system, multiple independent and long-time scale trajectories, and specialized analysis, we directly tracked and comprehensively characterized the oligomerization process. The mutation significantly enhanced both intra- and intermolecular interactions, promoting aggregation. It also altered the oligomerization pathways, as reflected in the distinct distribution across ten possible states formed by four Aβ16-22 peptides. Furthermore, while the wild-type peptide predominantly formed antiparallel β-sheets, the mutant favored parallel and mixed β-sheet arrangements. These results indicated that increased hydrophobicity and aromaticity facilitate more stable and polymorphic aggregation pathways. Our findings highlight the dominant role of hydrophobic interactions in early-stage Aβ aggregation and emphasize the therapeutic potential of targeting hydrophobic hotspots, such as the LVFF core, while accounting for structural polymorphism rather than focusing solely on disrupting electrostatic interactions.
Man et al. (Mon,) studied this question.