| Summary: | 博士 === 臺灣大學 === 化學研究所 === 98 === Prion proteins, which lead many mammal diseases from the abnormally structural variations, result in numerous scientific investigations in different aspects. Those proteins usually functionalize well in biological environment, called cellular prion protein (PrPC). Until main transformation on secondary structure to beta-sheet riched form, the infectious protein ''particles'' become scrapie prion protein (PrPSc) named after the first observed prion disease in sheep. Oligomer including several mis-folding prion would infects other normal cellular prion proteins and makes them aggregate in further. In the process of denaturation, the ratio of highly packed beta-sheets in prion proteins will increase, gradually and finally form the so-called amyloid fibrils. Amyloid fibrils are discovered in many neurodegeneration diseases. Therefore, figuring out the mechanism(s) of transformation between PrPC and PrPSc, the reason aggregation proceeds will be the first step to prevent and even to remedy this kind of diseases.
However, structural information from experimental data is limited and partial. Those parameters are the length and diameter of filaments from TEM, inter-atomic distances and backbone torsional angles from solid state NMR, and the deterministic secondary structure, etc. Those data can not give us the direct evidences in describing the system from single strand to extended beta-sheets with or without layer structure and from protofibers to mature fibers. Thus, molecular simulations with description of interactions in the system, will be an important way to sample and search the structures in potential energy surface. Then we may be able to comprehend how those relatively more stable states in the process of prion protein transformation.
We already got several information from investigation of human prion protein fragment 127-147 (huPrP127-147) and using those parameters during modeling the system. After modeling, we use molecular dynamics simulations as the way to find out the most stable structure and how the stripe formed as the TEM image. In our surprise, we get penne-like hyper-structure as the number of strands larger than 16. We think this spectacular model might be related to the initial state of the process forming protofibers.
On the other hand, research on the other prion system, hamster prion protein fragment 109-122 (HaPrP109-122), shows that there is an additional 8 cm-1 red-shift of amide I'' band of isotopically labeled AA specimen comparing with other samples of different labeling scheme. We believe the major reason of this red shift result from the transition dipole coupling (TDC) interaction of local stretching mode of labeled carbonyl carbon on Ala117 residue in-register to other one. But in this system, there might be contribution from inter-layer TDC. In order to clarify the source of major TDC effect, we use ab initio calculation of density funcational theory and classic model of dipolar coupling mechanism. The results show that intra-layer contribution is larger than inter-layer one in at least one order of magnitude.
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