Exploring the early steps of aggregation of amyloid-forming peptide KFFE

Abstract

It has been shown recently that even a tetrapeptide can form amyloid fibrils sharing all thecharacteristics of amyloid fibrils built from large proteins. Recent experimental studies alsosuggest that the toxicity observed in several neurodegenerative diseases, such asAlzheimer’s disease and Creutzfeldt–Jakob disease, is not only related to themature fibrils themselves, but also to the soluble oligomers formed early in theprocess of fibrillogenesis. This raises the interest in studying the early steps of theaggregation process. Although fibril formation follows the nucleation–condensationprocess, characterized by the presence of lag phase, the exact pathways remain to bedetermined. In this study, we used the activation–relaxation technique and ageneric energy model to explore the process of self-assembly and the structures ofthe resulting aggregates of eight KFFE peptides. Our simulations show, startingfrom different states with a preformed antiparallel dimer, that eight chains canself-assemble to adopt, with various orientations, four possible distant oligomericwell-aligned structures of similar energy. Two of these structures show a double-layerβ-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-raydiffraction; another two are mixtures of dimers and trimers. Our results also suggest thatoctamers are likely to be below the critical size for nucleation of amyloid fibrils for smallpeptides.