Modeling of Platinum-Aryl Interaction with Amyloid-ß Peptide
Modeling of Platinum-Aryl Interaction with Amyloid-ß Peptide
复制标题
铂-芳基与淀粉样蛋白-肽相互作用的建模
DOI：
10.1021/acs.jctc.5b01045
复制
发表时间：
2016
影响因子：
5.5
通讯作者：
Turner M
中科院分区：
文献类型：
--
作者：
Turner M
采用配体场分子力学（LFMM）、密度泛函理论（DFT）和半经验PM 7方法研究了两个Pt（II）-L体系与淀粉样β肽N端片段的结合，其中L = 2，2-联吡啶或1，10-菲咯啉.采用LFMM结合AMBER分子力学参数进行分子动力学模拟，探索肽的构象自由度。我们建立了一个建模协议，允许识别和分析有利的铂结合模式和肽构象。优选的结合模式被确定为每个研究的配体;金属配位通过Nε在两个配体的His残基中发生-His 6 ε-His 13 ε和His 6 ε-His 14 ε分别用于联吡啶和菲咯啉配体。观察到的不同配体的结合模式的变化表明，这些铂基结构的结合模式可以通过选择配体来控制。在bipy体系中，310 K下的Boltzmann布居由单一构象占据主导地位，而在菲咯啉体系中，三种构象对系综有显著贡献。这些构象的相对稳定性是由于通过Nε结合铂的固有稳定性以及微妙的氢键效应。
Ligand field molecular mechanics (LFMM), density functional theory (DFT), and semiempirical PM7 methods are used to study the binding of two Pt(II)-L systems to an N-terminal fragment of the amyloid-β peptide, where L = 2,2-bipyridyl or 1,10-phenanthroline. Molecular dynamics simulations are used to explore the conformational freedom of the peptide using LFMM combined with AMBER molecular mechanics parameters. We establish a modeling protocol, allowing for identification and analysis of favorable platinum-binding modes and peptide conformations. Preferred binding modes are identified for each ligand investigated; metal coordination occurs via Nε in His residues for both ligands - His6ε-His13ε and His6ε-His14ε for the bipyridyl and phenanthroline ligands, respectively. The observed change in binding mode for the different ligands suggests that the binding mode of these platinum-based structures can be controlled by the choice of ligand. In the bipy systems, Boltzmann population at 310 K is dominated by a single conformer, while in the phenanthroline case, three conformations make significant contributions to the ensemble. The relative stability of these conformations is due to the inherent stability of binding platinum via Nε in addition to subtle H-bonding effects.