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.