Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies
文献类型：期刊论文
| 作者 | Zuo, Zhili; Gang, Chen; Zou, Hanjun; Mok, Puah Chum; Zhu, Weiliang ; Chen, Kaixian; Jiang, Hualiang
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| 刊名 | COMPUTATIONAL BIOLOGY AND CHEMISTRY
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| 出版日期 | 2007-06 |
| 卷号 | 31期号:3页码:186-195 |
| 关键词 | homolgy modeling steered MD MM-PBSA free energy drug design |
| ISSN号 | 1476-9271 |
| DOI | 10.1016/j.compbiolchem.2007.03.007 |
| 文献子类 | Article |
| 英文摘要 | beta-secretase is a potential target for inhibitory drugs against Alzheimer's disease as it cleaves amyloid precursor protein (APP) to form insoluble amyloid plaques and vascular deposits in the brain. beta-secretase is matured from its precursor protein, called beta-secretase zymogen, which, different from most of other zymogens, is also partially active in cleaving APP. Hence, it is important to study on the mechanism of the zymogen's activation process. This study was to model the 3-D structure of the zymogen, followed by intensive molecular dynamics (MD) simulations to identify the most probable 3-D model and to study the dynamic structural behavior of the zymogen for understanding the effects of pro-segment on the function of the enzyme. The results revealed that the dropping in catalytic activity of the beta-secretase zymogen could be attributed to the occupation of the entrance of the catalytic site of the zymogen by its pro-segment. On the other hand, the partial catalytic activity of the zymogen could be explained by high fluctuation of the pro-segment in comparison with that of other zymogens, resulting in the occasionally exposure of the catalytic site for access its substrate APP. Indeed, steered MD (SMD) simulation revealed a weak pulling force at quasi-equilibrium state for the pro-segment of the zymogen leaving from the entrance, indicating that this swinging process could take place spontaneously. Furthermore, MM-PBSA calculation revealed a small change of free energy of 10.56 kal/mol between the initial and final states of the process of pro-segment swung outside the binding pocket of beta-secretase zymogen. These results not only account for the partial catalytic activity of P-secretase zymogen, but also provide useful clues for discovering new potent ligands, as new type of drug leads for curing Alzheimer's disease, to prevent the pro-segment of the zymogen from leaving its catalytic site. (c) 2007 Elsevier Ltd. All rights reserved. |
| WOS关键词 | AMYLOID PRECURSOR PROTEIN ; STRUCTURE-BASED DESIGN ; PARTICLE MESH EWALD ; PEPTIDOMIMETIC INHIBITORS ; FREE-ENERGIES ; SOLVENT ; RESOLUTION ; DISEASE ; SURFACE ; POTENT |
| WOS研究方向 | Life Sciences & Biomedicine - Other Topics ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000247289900005 |
| 出版者 | ELSEVIER SCI LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273240]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Mok, Puah Chum |
| 作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Singapore Polytech, Technol Ctr Life Sci, Singapore 139651, Singapore |
| 推荐引用方式 GB/T 7714 | Zuo, Zhili,Gang, Chen,Zou, Hanjun,et al. Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies[J]. COMPUTATIONAL BIOLOGY AND CHEMISTRY,2007,31(3):186-195. |
| APA | Zuo, Zhili.,Gang, Chen.,Zou, Hanjun.,Mok, Puah Chum.,Zhu, Weiliang.,...&Jiang, Hualiang.(2007).Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies.COMPUTATIONAL BIOLOGY AND CHEMISTRY,31(3),186-195. |
| MLA | Zuo, Zhili,et al."Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies".COMPUTATIONAL BIOLOGY AND CHEMISTRY 31.3(2007):186-195. |
入库方式： OAI收割
来源：上海药物研究所
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