A variational model for oligomer-formation process of GNNQQNY peptide from yeast prion protein Sup35.
Many human neurodegenerative diseases are associated with the aggregation of insoluble amyloid-like fibrous proteins. However, the processes by which the randomly diffused monomer peptides aggregate into the highly regulated amyloid fibril structures are largely unknown. We proposed a residue-level coarse-grained variational model for the investigation of the aggregation pathway for a small assembly of amyloid proteins, the peptide GNNQQNY from yeast prion protein Sup35. By examining the free energy surface, we identified the residue-level sequential pathways for double parallel and antiparallel β-peptides, which show that the central dry polar zipper structure is the major folding core in both cases. The critical nucleus size is determined to be three peptides for the homogeneous nucleation process, whereas the zig-zag growth pattern appears most favorably for heterogeneous nucleation. Consistent with the dock-and-lock mechanism, the aggregation process of free peptides to the fibril core was found to be highly cooperative. The quantitative validation with the computational simulations and experimental data demonstrated the usefulness of the proposed model in understanding the general mechanism of the amyloid fibril system.
Center for Computational Medicine and Bioinformatics, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
Xianghong
X
Qi
Liu
L
Hong
Yang
Y
Zhang
D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D010454:Peptide Termination Factors / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*
D009842:Oligopeptides; D010446:Peptide Fragments; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins