High-resolution molecular recognition of ligands using solution X-ray scattering

项目总结 蛋白质-配体相互作用是几乎所有生物有机体的基础，因此是主要的焦点 药物疗法。然而，由于目前可用数据的限制，这些相互作用很难研究 结构方法。蛋白质-配体复合体的三维原子结构显著增加了我们的 对分子识别的理解，导致了基于结构的药物设计及其 基本融入药物化学。X射线结晶学是研究结构的主要工具 大分子的测定，并能够阐明高分辨率的原子相互作用 蛋白质和配体，但受到实验限制，如结晶的瓶颈和 无法揭示动态的结构状态。溶液散射提供了一种对结构建模的机制 和分子在溶液中的动力学，然而目前的方法只提供低分辨率的信息，不足以 用于表征配体和蛋白质之间的原子水平相互作用。 在这里，我们提出了一系列结合了溶液散射和结构信息的新算法 通过结晶学等方法获得的高分辨结构和动力学 溶液中的蛋白质-配体复合体。这项提案的目标的成功完成将使 研究人员确定导致药物等配体分子识别的原子水平相互作用 和其他小分子。由于溶液散射实验可以在高通量下进行，因此这些 进展有望提高药物筛选和表征的速度。这些 洞察力最终将在开发新的疗法和改进治疗方法方面发挥重要作用 基于结构的药物设计，允许对多种疾病进行更具体和有效的治疗。

PROJECT SUMMARY Protein-ligand interactions are fundamental to virtually all biological organisms and thus are the primary focus of pharmaceutical therapies. Yet these interactions are difficult to study due to current limitations in available structural methods. 3D atomic structures of protein-ligand complexes have dramatically increased our understanding of molecular recognition, resulting in the development of structure-based drug design and its fundamental integration into medicinal chemistry. X-ray crystallography is the primary tool for structure determination of macromolecules and is capable of elucidating high-resolution atomic interactions between proteins and ligands, yet suffers from experimental limitations such as the bottleneck of crystallization and the inability to reveal dynamic structural states. Solution scattering provides a mechanism for modeling the structure and dynamics of molecules in solution, yet current methods only provide low-resolution information, insufficient for characterizing atomic level interactions between ligands and proteins. Here we propose a collection of new algorithms combining solution scattering with structural information obtained by methods such as crystallography for the determination of high-resolution structure and dynamics of protein-ligand complexes in solution. The successful completion of the aims of this proposal will enable researchers to identify the atomic-level interactions resulting in molecular recognition of ligands such as drugs and other small molecules. As solution scattering experiments can be performed in high-throughput, these developments promise to increase the rate at which pharmaceuticals can be screened and characterized. These insights will ultimately play an important role in developing novel therapeutics and improving approaches to structure-based drug design, allowing for more specific and effective treatments of a wide range of diseases.