Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors
文献类型：期刊论文
| 作者 | Yan, Chunli1; Xiu, Zhilong1; Li, Xiaohui1; Li, Shenmin2; Hao, Ce3,4; Teng, Hu1 |
| 刊名 | Proteins-structure function and bioinformatics
 |
| 出版日期 | 2008-10-01 |
| 卷号 | 73期号:1页码:134-149 |
| 关键词 | Histone deacetylase Histone deacetylase-like protein Molecular dynamics simulation Molecular mechanics-poisson-boltzmann surface area (mm-pbsa) method Molecular mechanics generalized born surface area (mm-gbsa) Mutagenesis Hydroxamic acid inhibitor |
| ISSN号 | 0887-3585 |
| DOI | 10.1002/prot.22047 |
| 通讯作者 | Xiu, zhilong(zhlxiu@dlut.edu.cn) |
| 英文摘要 | Histone deacetylases (hdacs) play an important role in gene transcription, and inhibitors of hdacs can induce cell differentiation and suppress cell proliferation in tumor cells. histone deacetylase1 (hdac1) binds suberanilohydroxamic acid (saha) and 7-phenyl-2, 4, 6-hepta-trienoyl hydroxamic acid (cg-1521) with moderately low affinity (delta g = -8.6 and -7.8 kcal mol(-1)). the structurally related (e)-2-(3-(3(hydro,hydroxyamino)-3-oxoprop-1-enyl)phenyl)-n-1,n-3-diphenyl- malonamide (sk-683), a trichostatin a (tsa)-like hdac1 inhibitor, and tsa are bound to the hdac1 with -12.3 and -10.3 kcal mol(-1) of delta g, higher binding free energies than saha and cg-1521. histone deacetylase-like protein (hdlp), an hdac homologue, shows a 35.2% sequence identity of hdlp and human hdac1. molecular dynamics simulation and the molecular mechanics/generalized-born surface area (mm-gbsa) free energy calculations were applied to investigate the factors responsible for the relatively activity of these four inhibitors to hdlp. in addition, computational alanine scanning of the binding site residues was carried out to determine the contribution components front van der waals, electrostatic interaction, nonpolar and polar energy of solvation as well as the effects of backbones and side-chains with the mm-gbsa method. mm-gbsa methods reproduced the experimental relative affinities of the four inhibitors in good agreement (r-2 = 0.996) between experimental and computed binding energies. the mm-gbsa calculations showed that, the number of hydrogen bonds formed between the hdlp and inhibitors, which varied in the system studied, and electrostatic interactions determined the magnitude of the free energies for hdlp-inhibitor interactions. the mm-gbsa calculations revealed that the binding of hdlp to these four hydroxamic acid inhibitors is mainly driven by van der waals/nonpolar interactions. this study can be a guide for the optimization of hdac inhibitors and future design of new therapeutic agents for the treatment of cancer. |
| WOS关键词 | ALANINE-SCANNING MUTAGENESIS ; CELL-DIFFERENTIATION ; CONTINUUM SOLVENT ; FORCE-FIELD ; BIOLOGICAL EVALUATION ; CYCLIC TETRAPEPTIDE ; LIGAND-BINDING ; TRICHOSTATIN-A ; HUMAN HDAC8 ; RESP MODEL |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| WOS类目 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000259114500014 |
| 出版者 | WILEY-BLACKWELL |
| URI标识 | http://www.irgrid.ac.cn/handle/1471x/2374106 |
| 专题 | 计算机网络信息中心 |
| 通讯作者 | Xiu, Zhilong |
| 作者单位 | 1.Dalian Univ Technol, Sch Environm & Biol Sci & Technol, Dept Biosci & Biotechnol, Dalian 116024, Peoples R China 2.Dalian Univ, Key Lab Bioorgan Chem, Dalian 116622, Peoples R China 3.Dalian Univ Technol, Sch Chem Sci & Engn, Dept Chem, Dalian 116024, Peoples R China 4.Chinese Acad Sci, CNIC, Virtual Lab Computat Chem, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yan, Chunli,Xiu, Zhilong,Li, Xiaohui,et al. Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors[J]. Proteins-structure function and bioinformatics,2008,73(1):134-149. |
| APA | Yan, Chunli,Xiu, Zhilong,Li, Xiaohui,Li, Shenmin,Hao, Ce,&Teng, Hu.(2008).Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors.Proteins-structure function and bioinformatics,73(1),134-149. |
| MLA | Yan, Chunli,et al."Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors".Proteins-structure function and bioinformatics 73.1(2008):134-149. |
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