コンピューティングを活用した寄生植物ストライガを抑制する生命機能分子の探索

利用计算寻找抑制寄生植物独脚金的生物功能分子

基本信息

批准号：
17F17819
负责人：
TAMA FLORENCE
金额：
$ 1.41万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2017
资助国家：
日本
起止时间：
2017-11-10 至 2018-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17F17819/
关键词：
striga MD simulations

项目摘要

Based on X-ray crystal structure of Striga receptor ShHTL5, homology models of ShHTL7 were developed and validated. In addition, models of a collection of experimentally investigated HTL7 mutants (amino acid residue changes in the receptor’s active site) were created. These structures were submitted to MD simulations to explore their structural flexibility. The analyses of resulting MD trajectories showed significantly higher plasticity of HTL7 protein helices that surround the active site of HTLs compared to HTL5. The degree of flexibility decreases with increasing number of single residue changes from HTL7 towards HTL5. The increased flexibility in HTL7 is found to be in accordance with experimental assay results that indicate that HTL7 is more promiscuous with regard to ligand binding compared to other HTLs.The developed homology models of HTL7 and the published structure of HTL5 were further used as basis for induced fit docking studies with experimentally validated active molecules. The purpose of these docking studies was to (i) computationally assess the structure-activity relationship of tested small molecules and Striga receptors and to identify essential protein-ligand interactions that lead to receptor modulation, and (ii) to create an ensemble of structural complexes with highly potent molecules for subsequent protein-ligand MD simulations. These could be used for the development of 3D dynophore models that would allow virtual screening of chemical libraries.

基于 Striga 受体 ShHTL5 的 X 射线晶体结构，开发并验证了 ShHTL7 的同源模型。此外，还创建了一组经过实验研究的 HTL7 突变体（受体活性位点的氨基酸残基变化）的模型。进行 MD 模拟以探索其结构灵活性，对所得 MD 轨迹的分析表明，与 HTL5 相比，HTL 活性位点周围的 HTL7 蛋白螺旋的可塑性明显更高。随着从 HTL7 到 HTL5 的单个残基变化数量的增加，灵活性的降低与实验测定结果一致，表明与其他 HTL 相比，HTL7 在配体结合方面更加混杂。所开发的同源性。 HTL7 模型和已发表的 HTL5 结构进一步用作与经过实验验证的活性分子进行诱导拟合对接研究的基础，这些对接研究的目的是 (i) 通过计算评估 HTL5 的结构-活性关系。测试了小分子和 Striga 受体，并确定了导致受体调节的重要蛋白质-配体相互作用，以及 (ii) 创建了具有高效分子的结构复合物集合，用于后续蛋白质-配体 MD 模拟。 3D 强效基团模型，可实现化学库的虚拟筛选。