title: Dead-end street of protein folding: thermodynamic rationale of amyloid fibril formation.
abstract: An increasing number of diseases, including Alzheimer's, have been found to be a result of the formation of amyloid aggregates that are practically independent of the original primary sequence of the protein(s). (Eakin, C. M.; Berman, A. J.; Miranker, A. D. Nat. Struct. Mol. Biol. 2006, 13, 202-208.) Consequently, the driving force of the transformation from original to disordered amyloid fold is expected to lie in the protein backbone, which is common to all proteins. (Nelson, R.; Sawaya, M. R.; Balbirnie, M.; Madsen, A. O.; Riekel, C.; Grothe, R.; Eisenberg, D. Nature 2005, 435, 773-778. Wright, C. F.; Teichmann, S. A.; Clarke, J.; Dobson, C. M. Nature 2005, 438, 878-881.) However, the exact explanation for the existence of such a "dead-end" structure is still unknown. Using systematic first principle calculations on carefully selected but large enough systems modeling the protein backbone we show that the beta-pleated sheet structure, the building block of amyloid fibers, is the thermodynamically most stable supramolecular arrangement of all the possible peptide dimers and oligomers both in vacuum and in aqueous environments. Even in a crystalline state (periodical, tight peptide attechment), the beta-pleated sheet assembly remains the most stable superstructure. The present theoretical study provides a quantum-level explanation for why proteins can take the amyloid state when local structural preferences jeopardize the functional native global fold and why it is a beta-pleated sheetlike structure they prefer.
authors.affiliation: Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös LorAnd University, Budapest, Hungary. perczel@chem.elte.hu
authors.forename: András
authors.initials: A
authors.lastname: Perczel
authors.forename: Péter
authors.initials: P
authors.lastname: Hudáky
authors.forename: Villö K
authors.initials: VK
authors.lastname: Pálfi
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D003460:Crystallization; D004583:Electrons; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D010455:Peptides