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

基于独脚金受体ShHTL 5的X-射线晶体结构，建立并验证了ShHTL 7的同源模型。此外，建立了一系列实验研究的HTL 7突变体（受体活性位点的氨基酸残基变化）的模型。这些结构被提交到MD模拟，以探索其结构的灵活性。所得MD轨迹的分析显示，与HTL 5相比，HTL 7蛋白螺旋围绕HTL的活性位点的可塑性显著更高。灵活性的程度随着从HTL 7到HTL 5的单个残基变化的数量的增加而降低。HTL 7的增加的灵活性被发现是根据实验测定结果，表明HTL 7是更混杂的配体结合相比，其他HTLsHTL 7和HTL 5的已发表的结构的同源性模型，进一步被用作基础与实验验证的活性分子的诱导拟合对接研究。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必要蛋白质-配体相互作用，以及（ii）创建具有高度有效分子的结构复合物的整体，用于随后的蛋白质-配体MD模拟。这些可用于开发3D动力团模型，从而允许虚拟筛选化学文库。

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.