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

项目摘要 蛋白质-配体相互作用是几乎所有生物有机体的基础，因此是主要焦点 药物治疗的方法。然而，由于目前可用的限制，这些相互作用很难研究 结构方法蛋白质-配体复合物的3D原子结构极大地增加了我们的研究。 对分子识别的理解，导致了基于结构的药物设计及其 药物化学的基础整合。X射线晶体学是研究晶体结构的主要工具 测定大分子，并能够阐明高分辨率原子之间的相互作用 蛋白质和配体，但受到实验的限制，如结晶的瓶颈和 无法显示动态结构状态。溶液散射提供了一种对结构进行建模的机制 和动态的分子在溶液中，但目前的方法只提供低分辨率的信息，不足 用于表征配体和蛋白质之间的原子水平相互作用。 在这里，我们提出了一个新的算法相结合的解决方案散射与结构信息的集合 通过晶体学等方法获得，用于确定高分辨率结构和动力学， 蛋白质-配体复合物。成功实现本提案的目标将使 研究人员确定原子水平的相互作用，导致分子识别配体，如药物 和其他小分子。由于溶液散射实验可以以高通量进行，因此这些 这些发展有望提高筛选和表征药物的速度。这些 这些见解最终将在开发新的治疗方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，允许更具体和更有效地治疗各种疾病。

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.