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CLC number: Q67

On-line Access: 2015-10-03

Received: 2015-05-02

Revision Accepted: 2015-08-04

Crosschecked: 2015-09-13

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 ORCID:

Hua Yu

http://orcid.org/0000-0002-1151-466X

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Journal of Zhejiang University SCIENCE B 2015 Vol.16 No.10 P.883-896

http://doi.org/10.1631/jzus.B1500106


Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides


Author(s):  Hua Yu, Mao-jun Wang, Nan-xia Xuan, Zhi-cai Shang, Jun Wu

Affiliation(s):  Department of Chemistry, Zhejiang University, Hangzhou 310027, China

Corresponding email(s):   shangzc@zju.edu.cn, wujunwu@zju.edu.cn

Key Words:  Binding affinity, EHD1 EH domain, Molecular dynamics simulation, Inhibitor design, Peptide


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Hua Yu, Mao-jun Wang, Nan-xia Xuan, Zhi-cai Shang, Jun Wu. Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides[J]. Journal of Zhejiang University Science B, 2015, 16(10): 883-896.

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author="Hua Yu, Mao-jun Wang, Nan-xia Xuan, Zhi-cai Shang, Jun Wu",
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volume="16",
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pages="883-896",
year="2015",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1500106"
}

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%T Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides
%A Hua Yu
%A Mao-jun Wang
%A Nan-xia Xuan
%A Zhi-cai Shang
%A Jun Wu
%J Journal of Zhejiang University SCIENCE B
%V 16
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%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1500106

TY - JOUR
T1 - Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides
A1 - Hua Yu
A1 - Mao-jun Wang
A1 - Nan-xia Xuan
A1 - Zhi-cai Shang
A1 - Jun Wu
J0 - Journal of Zhejiang University Science B
VL - 16
IS - 10
SP - 883
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%@ 1673-1581
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B1500106


Abstract: 
Objective: To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods: Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results: The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions: van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.

EHD1蛋白中的Eps15同源结构域与多种肽链相互作用的分子动力学模拟

目的:从结构和能量两个角度,探究EHD1蛋白中的Eps15同源结构域与不同肽链之间形成的复合物之间的亲和力差异的原因,为肽类抑制剂设计提供关键信息。
创新点:通过分子动力学模拟的方法,详细分析了三个复合物的结构差异。通过结合自由能计算及能量分解,定量对比了三条肽链中各个残基对复合物形成的贡献,确定了范德华相互作用以及侧面残基的氢键是影响亲和力大小的关键因素。
方法:用GROMACS程序对EHD1蛋白中的Eps15同源结构域与肽链形成的三个复合物进行各 60纳秒的分子动力学模拟,用AMBER程序中的MM/GBSA方法进行结合自由能计算和能量分解,用FoldX软件对三个复合物进行丙氨酸扫描实验。
结论:在对EHD1蛋白中的Eps15同源结构域进行高亲和力的肽类抑制剂设计时,范德华相互作用应该成为主要考虑因素。与蛋白质形成氢键的能力是侧面残基选择的参考因素。

关键词:亲和力;Eps15同源结构域;分子动力学模拟;抑制剂设计;肽

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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