Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies

doi:10.1016/j.compbiolchem.2007.03.007

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	Why does beta-secretase zymogen possess catalytic activity? Molecular modeling and molecular dynamics simulation studies
	Zuo, Zhili ; Gang, Chen ; Zou, Hanjun ; Mok, Puah Chum ; Zhu, Weiliang; Chen, Kaixian; Jiang, Hualiang
刊名	COMPUTATIONAL BIOLOGY AND CHEMISTRY
	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
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000247289900005
内容类型	期刊论文
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.