Molecular Simulations Reveal Terminal Group Mediated Stabilization of Helical Conformers in Both Amyloid-β42 and α-Synuclein.

The presence of partially structured helices in natively unfolded amyloid-β42 (Aβ42) and α-synuclein (αS) has been shown to accelerate fibrillation in the onset of Alzheimer's and Parkinson's disease, respectively. At the other extreme, folded stable helical conformers have also been reported to resist amyloid formation. Recent studies indicate that amyloidogenic aggregation can be impeded using small molecules that stabilize the α-helical monomers and switch off the neurotoxic pathway. We predict a common intrapeptide route to stabilization based on the plasticity of helical conformations of Aβ42 and αS as assessed through extensive atomistic molecular dynamics (MD) computer simulations (∼36 μs) across ten distinct protein force field and water model combinations. Computed free energies and interaction maps (not obtainable from experiments alone) show that flexible terminal groups (N-terminus of Aβ42 and C-terminus of αS) show a tendency to stabilize folded helical conformations in both peptides via primary hydrophobic interactions with central hydrophobic domains, and secondary salt bridges with other domains. These interactions confer aggregation resistance by decreasing the population of partially structured helices and are absent in control simulations of complete unfolding. Computed helical stability is also significantly reduced in terminal-deleted variants. The models suggest new strategies to tackle neurodegeneration by rationally re-engineering terminal groups to optimize their predicted ability to deactivate helical monomers.