Following the aggregation of amyloid-forming peptides by computer simulations.

There is experimental evidence suggesting that the toxicity of neurodegenerative diseases such as Alzheimer's disease may result from the soluble intermediate oligomers. It is therefore important to characterize extensively the early steps of oligomer formation at atomic level. As these structures are metastable and short lived, experimental data are difficult to obtain and they must be complemented with numerical simulations. In this work, we use the activation-relaxation technique coupled with a coarse-grained energy model to study in detail the mechanisms of aggregation of four lys-phe-phe-glu (KFFE) peptides. This is the shortest peptide known to form amyloid fibrils in vitro. Our simulations indicate that four KFFE peptides adopt a variety of oligomeric states (tetramers, trimers, and dimers) with various orientations of the chains in rapid equilibrium. This conformational distribution is consistent with all-atom molecular-dynamics simulations in explicit solvent and is sequence dependent; as seen experimentally, the lys-pro-gly-glu (KPGE) peptides adopt disordered structures in solution. Our unbiased simulations also indicate that the assembly process is much more complex than previously thought and point to intermediate structures which likely are kinetic traps for longer chains.