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学科主题: 基础医学
题名:
Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases
作者: Geng, Lingling1; Gao, Jian1; Cui, Wei1; Tang, Yancheng2; Ji, Mingjuan1; Chen, Bozhen1
关键词: Molecular dynamics ; Matrix metalloproteinase ; MMP-2-selective inhibitor APP-IP ; MM/GBSA
刊名: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
发表日期: 2012-12-01
DOI: 10.1007/s10822-012-9617-3
卷: 26, 期:12, 页:1327-1342
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Biophysics ; Computer Science, Interdisciplinary Applications
研究领域[WOS]: Biochemistry & Molecular Biology ; Biophysics ; Computer Science
关键词[WOS]: 1.8-ANGSTROM CRYSTAL-STRUCTURE ; PROTEIN-DERIVED INHIBITOR ; EXTRACELLULAR-MATRIX ; MOLECULAR-MECHANICS ; CATALYTIC DOMAIN ; ZINC-BINDING ; RAS-RAF ; COMPLEX ; COLLAGENASE ; INVASION
英文摘要:

In this work, selectivity mechanism of APP-IP inhibitor (beta-amyloid precursor protein-derived inhibitory peptide) over matrix metalloproteinases (MMPs including MMP-2, MMP-7, MMP-9 and MMP-14) was investigated by molecular modeling methods. Among MMPs, MMP-2 is the most favorable one for APP-IP interacting based on our calculations. The predicted binding affinities can give a good explanation of the activity difference of inhibitor APP-IP. In Comparison with MMP-2/APP-IP complex, the side chain of Tyr214(MMP-7) makes the binding pocket so shallow that the whole side chain of Tyr3(APP-IP) can not be fully embraced, thus unfavorable for the N-terminal of APP-IP binding to MMP-7. The poor selectivity of APP-IP toward MMP-9 is mainly related with the decrease of interaction between the APP-IP C-terminal and MMP-9 due to the bulky side chains of Pro193 and Gln199, which is in agreement with experiment. The mutations at residues P193A and Q199G of MMP-9 alternate the binding pattern of the C-terminal of APP-IP by forming two new hydrogen bonds and hydrophobic interactions with MMP-9. The mutants favor the binding affinity of MMP-9 largely. For MMP-14/APP-IP, the large steric effect of Phe204(MMP-14) and the weak contributions of the polar residues Asn231(MMP-14) and Thr190(MMP-14) could explain why MMP-14 is non-selective for APP-IP interacting. Here, the molecular modeling methods were successfully employed to explore the selective inhibitor of MMPs, and our work gives valuable information for future rational design of selective peptide inhibitors toward individual MMP.

语种: 英语
所属项目编号: 21173264 ; ZNWH-2011-011
项目资助者: National Natural Science Foundation of China ; Foundation of Knowledge Innovative Engineering of Chinese Academy of Sciences
WOS记录号: WOS:000312885200003
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/67761
Appears in Collections:基础医学院_期刊论文

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作者单位: 1.Chinese Acad Sci, Grad Univ, Sch Chem & Chem Engn, Beijing 100049, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Beijing 100191, Peoples R China

Recommended Citation:
Geng, Lingling,Gao, Jian,Cui, Wei,et al. Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2012,26(12):1327-1342.
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