Exploring the Influence of Unstable Regions of Human γD-Crystallin by Single-Point Mutations and Molecular Docking
| Autor: | Chun-Hsien Lo, 羅峻賢 |
|---|---|
| Rok vydání: | 2017 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 Cataract, an eye disease related to protein aggregation, is the leading cause of blindness world-wide. Factors that cause cataract include exposure of daylight, abnormal diet, drug intake, and diabe-tes. The underlying mechanism that leads to cataract is related to the aggregation of crystallin proteins. Therefore, understanding the structural stability of crystallin proteins to avoid aggregation is of fore-most important for the prevention of this sight-threatening disease. Human γD-crystallin (HγDC), a 173-residue protein, is abundant in the nucleus of human eye lens and is one of the major crystallin proteins involved in the age-related nuclear cataract. Previous studies showed the unstable regions of HγDC are residues 115-118. In the first part of this thesis, the structural stabilities and aggregation propensity of various HγDC mutants from the un-stable regions were investigated at the molecular level by multiple bioinformatics tools. The most sta-ble and unstable mutants were chosen through a consensus ranking method for further verification by molecular dynamics simulations (MDS). By combining the results of RMSD, native contact fraction, and prediction of aggregation propensity, we found that R116I and F117A have the highest and low-est aggregation propensity among the mutants studied, respectively; however, their structural stabilities were almost the same as the wildtype. Moreover, the degree of aggregation propensity was related to the fluctuation and hydrophobicity in the residues 115-118. In the second part of this thesis, attenpts were made to seek the possible inhibitors to prevent the HγDC from forming aggregates by molecular docking. According to the interaction analysis between HγDC and small molecules, we speculated that rosmarinic acid was the best inhibitory molecule in our study because of its binding to the residues 115-118 of HγDC. We believe the outcome from this research may help to achieve a better understanding of the structural integrity of HγDC and pave way for future work in the development of therapeutic strategies against cataract. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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