Protein Misfolding and Amyloid Formation for the Peptide GNNQQNY from Yeast Prion Protein Sup35: Simulation by Reaction Path Annealing

We study the early steps of amyloid formation of the seven residue peptide GNNQQNY from yeast prion-like protein Sup35 by simulating the random coil to β-sheet and α-helix to β-sheet transition both in the absence and presence of a cross-β amyloid nucleus. The simulation method at atomic resolution employs a new implementation of a Langevin dynamics “reaction path annealing” algorithm. The results indicate that the presence of amyloid-like cross-β-sheet strands both facilitates the transition into the cross-β conformation and substantially lowers the free energy barrier for this transition. This model systems allows us to investigate the energetic and kinetic details of this transition, which is consistent with an auto-catalyzed, nucleation-like mechanism for the formation of β-amyloid. In particular, we find that electrostatic interactions of peptide backbone dipoles contribute significantly to the stability of the β-amyloid state. Furthermore, we find water exclusion and interactions of polar side-chains to be driving forces of amyloid formation: the cross-β conformation is stabilized by burial of polar side-chains and inter-residue hydrogen bonds in the presence of an amyloid-like “seed”. These findings are in support of a “dry, polar zipper model” of amyloid formation.