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Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance
Zhang, Hong; Yao, Yao; Yang, Huibin1; Wang, Xia; Kang, Zhuo1; Li, Yan2; Li, Guohui3; Wang, Yonghua
KeywordMetallocarboxypeptidases Drug Resistance Potato Carboxypeptidase Inhibitor Molecular Dynamics Simulations Binding Free Energy
Source PublicationINSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
2012-08-01
DOI10.1016/j.ibmb.2012.04.005
Volume42Issue:8Pages:583-595
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology ; Entomology
WOS Research AreaBiochemistry & Molecular Biology ; Entomology
WOS KeywordPLANT PROTEINASE-INHIBITORS ; BINDING FREE-ENERGY ; HELICOVERPA-ARMIGERA ; CRYSTAL-STRUCTURE ; METALLOCARBOXYPEPTIDASES ; SIMULATIONS ; ADAPTATION ; INSIGHTS ; MACROMOLECULES ; DECOMPOSITION
AbstractAs one potent plant protease inhibitor, potato carboxypeptidase inhibitor (PCI) can competitively inhibit insect digestive metallocarboxypeptidases (MCPs) through interfering with its digestive system that causes amino acid deficiencies and leading to serious developmental delay and mortality. However, this effective biological pest control is significantly impaired by the PCI-resistant insect MCPs. Therefore, deep understanding of the resistant mechanism of insect MCPs is particularly necessary for designing new durable pest control regimen and developing effective pesticides. In this study, the binding of PCI and small molecular inhibitor THI to insect PCI-sensitive/-resistant MCPs and human MCP was investigated by docking, molecular dynamics (MD) simulations and thermodynamic analysis. The structural analysis from MD simulations indicates that the PCI-resistant mechanism of CPBHz is mainly dominated by the Trp277A, which changes the conformation of beta 8-alpha 9 loop and therefore narrow the access to the active site of CPBHz, prohibiting the entrance of the C termini tail of PCI. Additionally, the insertion of Gly247A weakens the stabilization of CPBHz and PCI through disrupting the hydrogen bond formation with its surrounding residues. Furthermore, the predicted binding free energies gives explanation of structure affinity relationship of PCI and THI with MCPs and suggest that the electrostatic energy is the main contribution term affecting the difference in binding affinities. Finally, the decomposition analysis of binding free energies infers that the key residues Glu72, Arg127, Ile247/Leu247 and Glu270 are critical for the binding of PCI/THI to MCPs. (C) 2012 Elsevier Ltd. All rights reserved.
Language英语
WOS IDWOS:000306207500006
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/138082
Collection中国科学院大连化学物理研究所
Affiliation1.Shenyang Res Inst Chem Ind Co Ltd, State Key Lab Discovery & Dev Novel Pesticide, Shenyang 110000, Peoples R China
2.Dalian Univ Technol, Sch Chem Engn, Dalian 116012, Peoples R China
3.Chinese Acad Sci, Lab Mol Modeling & Design, Dalian 116024, Liaoning, Peoples R China
Recommended Citation
GB/T 7714
Zhang, Hong,Yao, Yao,Yang, Huibin,et al. Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance[J]. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY,2012,42(8):583-595.
APA Zhang, Hong.,Yao, Yao.,Yang, Huibin.,Wang, Xia.,Kang, Zhuo.,...&Wang, Yonghua.(2012).Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance.INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY,42(8),583-595.
MLA Zhang, Hong,et al."Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance".INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 42.8(2012):583-595.
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