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Conformational flexibility of β-secretase: molecular dynamics simulation and essential dynamics analysis

Acta Pharmacologica Sinica 2004年第6期25卷 3-11页

作者： Bing XIONG, Xiao-qin HUANG, Ling-ling SHEN, Jian-hua SHEN 2,Xiao-min LUO, Xu SHEN, Hua-liang JIANG2, Kai-xian CHENDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 中科院上海生命科学院 State Key Laboratory of Drug Research CAS 上海 201203

AIM: Based on the structural analysis to reveal the mechanism of ligand binding to b-secretase and the specificityof each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free b-secretase andligand bound b-secretase. The trajectories were analyzed using the essential dynamics, and the significant confor-mational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDomanalyses clearly showed that the b-secretase experienced a large conformational change upon the substrate orinhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate theligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysisrevealed that residues at P2, P1, and P1 positions of the inhibitor were very important for the binding, and residuesat P2 and P3 positions may be modified to improve the binding specificity. S3 subsite of the enzyme still hadspace to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented hereis valuable and could be used to identify small molecular inhibitors of b-secretase.

关键词： molecular dynamics secretase essential dynamics computer simulation Alzheimer disease

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Molecular dynamics simulations investigation of Neocarzinostatin Chromophore releasing pathways from the Holo-NCS protein

Molecular dynamics simulations investigation of Neocarzinost...

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第十一次中国生物物理学术大会暨第九届全国会员代表大会

作者： Xi Zhao 1 ,Song Wang 1 ,Xue-feng Gao 2 ,Xu-ri Huang 1 *,Chia-chung Sun 1 1 State Key Laboratory of Theoretical and Computational Chemistry,Institute of Theoretical Chemistry,Jilin University,Changchun 130023,People’s Republic of China 2 College of L ife Science,Jilin University,Changchun 130023,People’s Republic of China

＜正＞The enediyne ring chromophore with strong DNA cleavage activity of neocarzinostatin is labile and therefore stabilization by forming the complex(carrying protein+chromophore:

关键词： Neocarzinostatin enediyne ring chromophore release molecular dynamics force-probe molecular dynamics essential dynamics

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