Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils

Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils.: Several peptides and proteins have been shown to convert from their soluble forms into highly ordered fibrillar aggregates, known as amyloid fibrils. It has also been realised that the formation of amyloid fibrils is often preceded by the appearance of small but highly organised oligomeric assemblies. Interest in these low molecular weight oligomers has increased considerably since these molecular species have been detected in the brains of patients suffering from Alzheimer disease. Evidence is accumulating concerning the ability of the low molecular weight oligomers formed by the Aβ peptide to specifically disrupt cognitive function. To increase our understanding of this phenomenon, we describe in this paper the early stages of the oligomerization process of two fragments (Aβ16–22 and Aβ25–35) of the Aβ peptide, by exploiting the possibility provided by computer simulations to describe aggregation reactions at the molecular level. Our results suggest that the ability of many diverse peptides and proteins to form amyloid fibrils, as well as the inherent toxicity of many oligomeric assemblies, are a consequence of the tendency of the backbone of polypeptide chains to form hydrogen bonds, and of the outcome of the competition between hydrophobic and hydrogen bonding forces.