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

淀粉样变性疾病是一个主要的健康问题，包括阿尔茨海默氏症、帕金森氏病和亨廷顿病等神经退行性疾病，以及II型糖尿病和传染性普恩病毒疾病，如克雅病(CJD)。它们的特点是在细胞内和细胞外基质中沉积大量纤维状蛋白质聚集体，被认为导致细胞死亡并导致观察到的病理。这些纤维的组成纤维具有共同的长程有序的β-折叠结构，尽管它们能够由许多不同的蛋白质形成。最近，人们的注意力已经转移到前体可溶低聚物种类上，作为这些疾病的毒物。然而，这些低聚物中长程有序的确切结构和程度尚未确定，很难使用现有的生物物理技术进行探索，阻碍了针对该病现阶段的药物开发。我的研究员将利用太赫兹频域光谱(THz-TDS)来研究淀粉样蛋白纤维及其前体的长程有序性。这将得到拉曼光谱和分子模拟计算的补充，以了解这类重要的生物分子内分子间和分子内的相互作用。THz-TDS是一种新兴的技术，被证明对有机晶体化合物的研究特别重要。这是因为太赫兹光谱已经被证明可以激发分子间的振动，因此不仅可以探测化学成分，而且对晶体结构的微小变化也非常敏感。在团契期间，我将开发新的太赫兹频谱技术。例如，包括偏振敏感检测在内的THz频率将首次允许获得与分子手性有关的光谱信息，包括蛋白质和小肽的二级结构。

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.