Novel vibrational spectroscopic techniques: long-range order in amyloid fibrils

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Amyloid diseases are a major health problem and include neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as type II diabetes and infectious prion diseases, such as Creutzfeldt-Jakob disease (CJD). They are characterised by the deposition of large fibrillar aggregates of protein, both within cells and in the extra cellular matrix, that were thought to cause cell death and result in the observed pathology. The constituent fibres of these fibrils have a common beta-sheet architecture with long-range order despite being able to form from many different proteins. More recently, attention has shifted to precursor soluble oligomer species as the toxic agents in these diseases. However, the precise structure and degree of long-range order in these oligomers has not yet been determined and is difficult to probe using existing biophysical techniques, hampering the development of drugs targeted at this stage of the disease. My Fellowship will make use of terahertz frequency time-domain spectroscopy (THz-TDS) to study long-range order of amyloid fibrils and their precursors. This will be complemented by Raman spectroscopy and molecular modelling calculations to gain an understanding of the inter- and intra-molecular interactions within this important class of biological molecules. THz-TDS is an emerging technique that is proving to be of particular importance for the investigation of organic crystalline compounds. This is because THz spectroscopy has been shown to excite inter-molecular vibrations, thus not only probing chemical composition, but also proving to be extremely sensitive to small changes in crystalline structure. During the Fellowship, I will develop new THz frequency spectroscopic techniques. For example, the inclusion of polarisation sensitive detection will, for the first time at THz frequencies, allow spectroscopic information to be obtained related to the chirality of the molecules, including the secondary structure of proteins and small peptides.