Developing a theoretical framework for understanding amyloid aggregation

The phenomenon of protein aggregation has been recently associated with a variety of human disorders that affect large sections of the population worldwide. These pathological conditions, which include Alzheimer's and Parkinson's diseases, type II diabetes and the spongiform encephalopathies, are rapidly becoming one of the most important group of pathologies in the developed world in terms of incidence and social costs.It has been demonstrated for several proteins that amyloid fibril formation is preceded by the formation of metastable, non-fibrillar forms often referred to as protofibrils. In addition, detailed biophysical studies are beginning to identify the formation of further smaller oligomeric species that precede the formation of the protofibrils. These oligomers, which appear to be composed largely of molecules that have a relatively disorganised structure, subsequently convert into protofibrils containing extended regions of beta structure. The aim of this project is to use computer simulations to establish a general framework to understand the relationships between the multiple different aspects of the aggregation process. In particular, as the aggregation process can lead either to amorphous or to fibrillar deposits, depending on the conditions of the experiment. It is important to identify the factors that determine these outcomes. The amorphous state is characterised by the absence of an overall order. Furthermore, this state appears often to be off equilibrium. In order to obtain more insight into the process of fibril formation, it is important to understand how peptides and proteins reorganize themselves within amorphous aggregates, as the internal dynamics may very slowly drive the amorphous state, towards more ordered assemblies.An even more important aspect of the approach that we propose, which we will be able to study in the second stage of the project, is the possibility to characterise the mechanism of toxicity of the small oligomeric aggregates of the A-beta(25-35) peptide, which as of now, is still very little understood. It is of the utmost importance to investigate also whether a structural modification in these large oligomers can lead to the definition of the critical nucleus, i.e. the critical nucleus it is not defined just by the number of peptides but also by their structure.Amyloid aggregates are known to be formed preferentially by proteins of the same type, or of high sequence homology. Considering that the fibril brakes more often where a defect is present, rather then in a homogeneous place, removing this way the impurity from its structure, I want to investigate whether this hypothesis is enough to explain the homogeneity of fibrillar structures. If verified this would be of crucial importance for the drug design world because it would give a new light into the beta-breakers mechanism.Finally, I want to investigate the aggregation propensity of a polypeptide and its D-amino acid correspondent.