Bromodomains识别并结合配体的机理研究
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摘要
关于酵母重组蛋白内的Bromodomain识别乙酰化赖氨酸的研究近年来受到广泛的关注,但是其识别配体并与之相紧密结合的机理有待进一步的研究。本文采用2015年开发的结合位点拓扑学方法(FCTM)和分子动力学模拟的方式对Bromodomains识别并结合配体的机理进行了充分研究,其中分子动力学模拟时间达24 ns。通过FCTM方法发现结合位点的几何结构具有高度的凹性,且其alphaspace达到了131。分子动力学模拟的结果显示:在模拟的过程中结合位点表面的脯氨酸(Pro66)始终对配体保持着强的分子间相互作用,同时pocket内的水分子分布对配体的氢键网络也一直存在影响。以上结果表明Bromodomains识别并结合配体有两个重要因素:蛋白结构域自身的几何结构和配体受到来自于结合位点表面的氨基酸分子相互作用和pocket内水分子的氢键网络作用。
The research of the recognition of acetyl-lysine through Bromodomains in yeast remodeler has attracted wide attention in recent years. However, the mechanism of recognition and combination between Bromodomains and ligands needs further study. Fragment-centric topographical mapping(FCTM) and molecular dynamics simulation were used to study the mechanism in this paper, in which the simulation time was 24 ns. The geometric structure of the binding sites was highly concave and its alphaspace reached 131 by FCTM. The results of the molecular dynamics simulation show that the proline(Pro66) on the surface of combinational site always maintained a strong intermolecular interaction with the ligand during the simulation, and the distribution of water molecules within the pocket also existed on the hydrogen bond network of the ligand. The above results indicate that there are two important factors of Bromodomains to identify and bind ligands: The geometric structure of the protein domain itself and the continuous interaction of ligands with amino acid molecules on the surface of the binding site and pocket internal water molecules.
The research of the recognition of acetyl-lysine through Bromodomains in yeast remodeler has attracted wide attention in recent years. However, the mechanism of recognition and combination between Bromodomains and ligands needs further study. Fragment-centric topographical mapping(FCTM) and molecular dynamics simulation were used to study the mechanism in this paper, in which the simulation time was 24 ns. The geometric structure of the binding sites was highly concave and its alphaspace reached 131 by FCTM. The results of the molecular dynamics simulation show that the proline(Pro66) on the surface of combinational site always maintained a strong intermolecular interaction with the ligand during the simulation, and the distribution of water molecules within the pocket also existed on the hydrogen bond network of the ligand. The above results indicate that there are two important factors of Bromodomains to identify and bind ligands: The geometric structure of the protein domain itself and the continuous interaction of ligands with amino acid molecules on the surface of the binding site and pocket internal water molecules.
引文
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[3]BRAND M, MEASURES A M, WILSON B G, et al. Small molecule inhibitors of bromodomain acetyl-lysine interactions[J]. American Chemical Society, 2015, 10(17): 22-39.DOI: 10.1021/cb500996u.
[4]ROOKLIN D, WANG C, KATIGBAK J, et al. AlphaSpace: Fragment-centric topographical mapping to target protein-protein interaction interfaces[J]. Chemical Information and Modeling, 2015, 55(15): 1585-1599.DOI: 10.1021/acs.jcim.5b00103.
[5]FILIPPAKOPOULOS P, PICAUD S, MANGOS M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family[J]. Cell, 2012, 149(18): 214-231.DOI: 10.1016/j.cell.2012.02.013.
[6]WANG J. Molecular dynamics simulations of a protein crystal[J]. Bioenergetics: Open Access, 2014, 02(3):1-3.DOI: 10.4172/2167-7662.1000e117 .
[7]MCDOWELL S E, SPACKOVA N, SPONER J, et al. Molecular dynamics simulations of RNA: an in silico single molecule approach[J]. Biopolymers, 2007, 85(27): 1-27.DOI: 10.1002/bip.20620.
[8]NEIRA J L. NMR as a tool to identify and characterize protein folding intermediates[J]. Archives of Biochemistry and Biophysics, 2013, 531(10): 90-99.DOI: 10.1016/j.abb.2012.09.003.
[9]WANG H, CHEN Y, HUANG C, et al. Insight into the function of the key residues in the binding clefts of the substrate with CBM4-2 of xylanase Xyn10A by molecular modeling and free energy calculation[J]. Computational and Theoretical Chemistry, 2017, 1111(6):14-19.DOI:10.1016/j.comptc.2017.03.024.
[10]KOVERMANN M, ROGNE P, WOLF-WATZ M. Protein dynamics and function from solution state NMR spectroscopy[J]. Quarterly Reviews of Biophysics, 2016, 49(43):1-43.DOI: 10.1017/S0033583516000019.
[11]WEN B, ZHANG L, WANG D, et al. The distribution of excess carriers and their effects on water dissociation on rutile (110) surface[J]. Computational Materials Science, 2017, 136(7):150-156.DOI: 10.1016/j.commatsci.2017.04.037.
[12]刘畅,刘安.生物信息学分析RIPK4的分子结构与功能[J].生物信息学,2018,16(8):105-113.DOI: 10.3969/j.issn.1672-5565.201708006 . LIU Chang, LIU An. Bioinformatics analysis of the structure and function of RIPK4[J]. Chinese Journal of Bioinformatics, 2018, 16(8):105-113.DOI:10.3969/j.issn.1672-5565.201708006.