Protein Aggregation and Amyloid Formation

In addition to defining their molecular structures, it is of considerable interest to understand the physical properties of the fibrils and the nature of the forces that lead to their stability. To this end, we have been studying a range of different fibrils by means of experimental approaches originally developed within the rapidly developing field of nanotechnology, such as atomic force microscopy (AFM), in conjunction with computer simulation methods [35]. 

Our findings reveal that amyloid fibrils represent a well-defined class of highly organised materials with similar physical properties that can be compared and contrasted on the nanometre scale with well-established types of more conventional materials [35]. Specifically, the core structure of the fibrils is stabilised primarily by interactions, particularly hydrogen bonds, involving the polypeptide main chain (Fig. 13.5). As the main chain is common to all 

Even though the ability to aggregate to form amyloid fibrils appears to be generic, the propensity to do so under given circumstances can vary dramatically between different sequences [5]. It has proved possible to correlate the relative aggregation rates of a wide range of peptides and proteins with 

The propensities of folded proteins to aggregate will therefore depend on the accessibility of such aggregation-prone species, a conclusion that is clearly demonstrated by detailed studies of the amyloidogenic mutational variants of lysozyme, which we have found to decrease the stability and cooperativity of the native state (Fig. 13.4) [40-43]. Indeed, these experiments show that the effect of the disease-associated mutations is to decrease the energy difference between the native state and the intermediates populated in the normal folding of the protein, such that the latter are accessible to a much greater extent in the variants than in the wild-type protein [40]. The large mass of evidence now accumulated from studies of lysozyme has provided detailed 

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Auer, S., Dobson, C.M., and Venndruscolo, M. "Characterisation of the nucleation barriers for protein aggregation and amyloid formation". Hum. Front. Sci. Program J. 1,137146 (2007). 

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