Neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (IDPs), usually mediated by hydrophobic protein-protein interactions. There is mounting evidence that formation of alpha -helical intermediates is an early event during self-assembly of amyloid-beta 42 (A beta 42) and alpha -synuclein (alpha S) IDPs in Alzheimer's and Parkinson's disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both A beta 42 and alpha S. Our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (N-terminus of A beta 42 and C-terminus of alpha S). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both A beta 42 and alpha S peptides. The inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. This approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core.
