Folding of amyloidogenic protein and human telomerase RNA pseudoknot.

摘要

Understanding amyloid formation remains as one of the most challenging topics in current field of biochemistry and biophysics. My simulations of the folding of amyloid-β (Aβ) monomers have provided good agreement with experiments and other computational works. Employed novel data structure and algorithm, my study has revealed possible conformations adopted by Aβ monomers, which provide more structural information than other expensive computational works. Based on simulations, I propose a model of the monomer conformation which is supported by experimental data. Residues in the regions of characteristic turn and extended conformation may serve as a key site in the formation of dimers, trimers, and possible oligomers, and can be used as starting points for further investigation on aggregation.;The stabilities of β-sheet and two conformations of α-sheet in solution phase are investigated using quantum-mechanical approach. While β-sheet stays the most stable conformation, α-sheet featured with bifurcated H-bonds is distorted after stages of geometry optimization in solution. Whether α-sheets with longer chains would be increasingly favorable in water relative to the increase in internal energy of the chain needs further investigation.;Probabilistic RoadMap algorithm is applied to the search of folding reaction pathways in the complete ensembles of a synthetic oligonucleotide (PK 5), wild type human telomerase RNA pseudoknot (PKWT), and mutants of PKWT. Detailed networks showing folding routes from all unfolded conformations to the native conformations have been constructed. A likely short-lived but essential intermediate state has been identified. The study also revealed alternative folding pathways that have not been observed before.