De novo designed peptide-based amyloid fibrils.
Identification of therapeutic strategies to prevent or cure diseases associated with amyloid fibril deposition in tissue (Alzheimer's disease, spongiform encephalopathies, etc.) requires a rational understanding of the driving forces involved in the formation of these organized assemblies rich in beta-sheet structure. To this end, we used a computer-designed algorithm to search for hexapeptide sequences with a high propensity to form homopolymeric beta-sheets. Sequences predicted to be highly favorable on this basis were found experimentally to self-associate efficiently into beta-sheets, whereas point mutations predicted to be unfavorable for this structure inhibited polymerization. However, the property to form polymeric beta-sheets is not a sufficient requirement for fibril formation because, under the conditions used here, preformed beta-sheets from these peptides with charged residues form well defined fibrils only if the total net charge of the molecule is +/-1. This finding illustrates the delicate balance of interactions involved in the formation of fibrils relative to more disordered aggregates. The present results, in conjunction with x-ray fiber diffraction, electron microscopy, and Fourier transform infrared measurements, have allowed us to propose a detailed structural model of the fibrils.
López De La Paz
Manuela
M
European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany Europe. delapaz@embl-heidelberg.de
Goldie
Kenneth
K
Zurdo
Jesús
J
Lacroix
Emmanuel
E
Dobson
Christopher M
CM
Hoenger
Andreas
A
Serrano
Luis
L
D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D017076:Computer-Aided Design; D008854:Microscopy, Electron; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013816:Thermodynamics; D014961:X-Ray Diffraction
D000682:Amyloid; D009842:Oligopeptides