Characterization of Amyloidogenic Peptide Aggregability in Helical Subspace

Prototypical amyloidogenic peptides amyloid-β (Aβ) and α-synuclein (αS) can undergo helix-helix associations via partially folded helical conformers, which may influence pathological progression to Alzheimer's (AD) and Parkinson's disease (PD), respectively. At the other extreme, stable folded helical conformers have been reported to resist self-assembly and amyloid formation. Experimental characterisation of such disparities in aggregation profiles due to subtle differences in peptide stabilities is precluded by the conformational heterogeneity of helical subspace. The diverse physical models used in molecular simulations allow sampling distinct regions of the phase space and are extensive in capturing the ensemble of rich helical subspace. Robust and powerful computational predictive methods utilizing network theory and free energy mapping can model the origin of helical population shifts in amyloidogenic peptides, which highlight their inherent aggregability. In this chapter, we discuss computational models, methods, design rules, and strategies to identify the driving force behind helical self-assembly and the molecular origin of aggregation resistance in helical intermediates of Aβ42 and αS. By extensive multiscale mapping of intrapeptide interactions, we show that the computational models can capture features that are otherwise imperceptible to experiments. Our models predict that targeting terminal residues may allow modulation and control of initial pathogenic aggregability of amyloidogenic peptides.