Development of Computational Toolset for Structural Systems Pharmacology

项目总结/摘要 蛋白质与其配体的特异性相互作用是生物学功能的起源， 活的有机体这些分子构象发生在蛋白质的局部表面区域。随着快速增长 在高分辨率蛋白质结构的数量和蛋白质结构预测的令人印象深刻的进展， 大多数生物体蛋白质的完整三维结构信息可望得到 很快我们先前的研究表明，类似的结合位点发生在非同源蛋白质结构中， 使得从蛋白质-配体复合物结构预测配体结合位点和配体结构成为可能， 通过比较它们的结合位点来检索蛋白质数据库。在此基础上，我们的目标是建立一个高- 基于结构的蛋白质-配体相互作用研究和药物发现的性能计算工具集. 利用生物大分子中蛋白质-配体相互作用的局部结构模式， 结构数据和检测蛋白质结构之间的保守局部区域。在AIM 1中，我们将开发 G-PLI-预测器，用于预测硬靶标的配体结合位点、推定配体结构和蛋白质功能 并使用基于化学片段模板的方法设计新的配体。在AIM 2中，我们将开发G- LoSALR，我们的局部结构对齐工具G-LoSA的粗粒度版本，和G-LBS-Refiner， 一种基于分子动力学模拟的约束势引导的构象采样方法 从结构模板，以提高性能的结构库搜索。G-LoSALR将提供耐受性， 蛋白质结构的构象变化和预测蛋白质模型中的结构错误 对齐和相似性度量。G-LBS-Refiner将提供更可靠的结合位点构象， 从apo结构或通过改进低分辨率蛋白质模型产生全构象。在AIM 3中，我们 将开发G-Promis，一种蛋白质组学规模的配体混杂预测方法。G-Promis将执行所有 查询结合位点结构与蛋白质组中每个蛋白质的整个表面的结构比较 构建文库以鉴定一组潜在蛋白质靶，然后检查近似结合亲和力 在查询配体和靶蛋白之间。这些Web服务和/或独立工具包将免费提供给 提供给所有学术用户和非营利机构。该研究将提供可靠和 一般计算方法的学生和研究人员在生物界和其他学科， 能够促进关于蛋白质-配体相互作用的协同科学研究和教育， 药物开发

PROJECT SUMMARY/ABSTRACT The specific interactions of proteins with their ligands are an origin of biological functions that are essential for living organisms. These molecular recognitions occur in local surface regions of proteins. With a rapid increase in the number of high-resolution protein structures and impressive advances in protein structure prediction, complete three-dimensional structural information of most organismal proteins is expected to be available soon. Our previous study indicates that similar binding sites occur in non-homologous protein structures, making it feasible to predict ligand binding sites and ligand structures from protein-ligand complex structures in the Protein Data Bank by comparing their binding sites. Based on these, our goal is to develop a high- performance computational toolset for structure-based protein-ligand interaction studies and drug discovery at the proteomic level by utilizing the local structural patterns of protein-ligand interactions from big biomolecular structure data and by detecting conserved local regions between protein structures. In AIM 1, we will develop G-PLI-Predictor to predict ligand binding sites, putative ligand structures, and protein functions for hard targets and to design new ligands using a chemical fragment template-based approach. In AIM 2, we will develop G- LoSALR, a coarse-grained version of our local structure alignment tool G-LoSA, and G-LBS-Refiner, a molecular dynamics simulation-based conformation sampling method guided by restraint potentials derived from structure templates to improve performance in structure library search. G-LoSALR will provide tolerance to conformational variations in protein structures and structural errors in predicted protein models upon structure alignment and similarity measurement. G-LBS-Refiner will provide more reliable binding site conformations by generating holo-conformations from an apo-structure or by refining low-resolution protein models. In AIM3, we will develop G-Promis, a proteomic-scale ligand promiscuity prediction method. G-Promis will perform all structure comparisons of a query binding site structure with the whole surfaces of each protein in the proteome structure library to identify a set of potential protein targets and then examine approximate binding affinities between a query ligand and the target proteins. These web services and/or standalone toolkits will be freely available to all academic users and not-for-profit institutions. The proposed research will provide reliable and general computational methods to students and researchers in the biology community and other disciplines, enabling to foster synergistic scientific research and education on protein-ligand interactions and facilitating drug development.