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

基于Striga受体ShHTL5的x射线晶体结构，建立并验证了ShHTL7的同源性模型。此外，还建立了一系列HTL7突变体（受体活性位点的氨基酸残基变化）的模型。将这些结构提交给MD模拟以探索其结构灵活性。由此产生的MD轨迹分析表明，与HTL5相比，HTL7蛋白螺旋在HTLs活性位点周围的可塑性明显更高。从HTL7到HTL5，随着单个残留物变化数量的增加，灵活性程度降低。HTL7的灵活性增加与实验分析结果一致，表明HTL7与其他htl相比在配体结合方面更具混杂性。建立的HTL7同源性模型和已发表的HTL5结构进一步作为与实验验证的活性分子诱导拟合对接研究的基础。这些对接研究的目的是(i)计算评估测试的小分子和Striga受体的结构-活性关系，并确定导致受体调节的基本蛋白质-配体相互作用，以及（ii）创建具有高效分子的结构复合物的集合，用于随后的蛋白质-配体MD模拟。这些可以用于开发3D动态峰模型，从而可以对化学文库进行虚拟筛选。

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.