Temperature-Dependent Dynamics of Aβ42 and α-Synuclein Monomers and Early Oligomerization of Aβ42: Shared Residues...

We used molecular dynamics simulations to investigate how temperature modulates hydrophobic interactions and β-sheet formation in the CHARMM36m model of intrinsically disordered proteins, focusing on a monomer of amyloid-beta (Aβ42) and α-synuclein, as well as a dimer and tetramer of Aβ42. For the isolated monomers, increasing temperature leads to an increase in intramolecular contacts, promoting hydrogen bonding and secondary-structure reorganization toward β-sheet and turn motifs. Analysis of the dimer and tetramer of Aβ42 reveals increased conformational heterogeneity at high temperatures, suggesting a smaller-than-expected configurational entropy penalty upon association. Thus, whereas monomers undergo temperature-induced compaction, enhancing intramolecular interactions, including the formation of β-sheets, in the dimer and tetramer, hydrophobic stabilization is redirected toward aggregation, promoting cross-β-sheet formation, peptide elongation, and the emergence of spherical conformations. Notably, the residues that stabilize intramolecular β-sheets in the monomer (approximately sequences 16-22 and 29-36) largely overlap with those that form cross-β-sheet motifs in the aggregates, suggesting that intramolecular β-sheet formation is intrinsically linked to aggregation propensity. These results, in close agreement with earlier NMR measurements of the monomer and protofibrils, reveal a competition between intra- and intermolecular hydrophobic interactions, with intermolecular interactions ultimately becoming more favorable than the intramolecular interactions that stabilize monomer solvation.