The assembly of normally soluble proteins into large fibrils, known as amyloid aggregation, is associated with a range of pathologies, including Alzheimer’s and Parkinson’s diseases. It has proven to be very challenging to experimentally characterize the mechanisms of amyloid formation; this is crucial for influencing the pathological processes in a rational manner.
Computer simulations, in combination with quantitative experiments, can provide invaluable insight in this case. Substantial evidence shows that disordered pre‐fibrillar oligomers − not the fully grown amyloid fibrils − are cytotoxic and involved in pathological processes. Yet, their relationship to fibrils is not well understood. Using computer simulations, we showed that at physiological conditions, small disordered oligomers serve as nucleation centres for fibrils, and are crucial on‐pathway species to amyloid formation [1].
Furthermore, recent experiments have revealed that amyloid fibrils are able to catalyze formation of their copies from soluble peptides. By combining simulations and kinetic theory, with biosensing experiments and kinetic measurements of Alzheimer’s Aβ40 peptide aggregation, we proposed a mechanistic explanation for the self‐replication of protein fibrils.
We find that this intricate process is governed by a single physical determinant − the adsorption of monomeric proteins onto the surface of fibrils [2]. Such mechanistic understanding not only has implications for future efforts to control pathological protein aggregation, but is also of interest for the rational assembly of nanomaterials, where achieving self‐replication is one of the unfulfilled goals.