Electric Field-stimulated Protein Mechanics

电场刺激的蛋白质力学

• 批准号: 10093087
• 负责人: RAMA RANGANATHAN
• 金额: $ 30.45万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093087
• 关键词: Address; Area; Automobile Driving; Biological; Biological Process; Catalysis; Characteristics; Charge; Collaborations; Collection; Communities; Complex; Coupled; Crystallization; Crystallography; Data; Data Analyses; Data Collection; Development; Disease; Engineering; Enzymes; Exposure to; Goals; Human; Image; Infrastructure; Ion Channel; Knowledge; Measurement; Mechanics; Membrane Proteins; Methods; Microfluidics; Modeling; Molecular; Molecular Conformation; Molecular Machines; Motion; Mutagenesis; Pattern; Pharmacology; Physiologic pulse; Physiological; Process; Protein Dynamics; Protein Family; Proteins; Protocols documentation; Pump; Reaction; Regulation; Resolution; Roentgen Rays; Sampling; Science; Series; Services; Signal Transduction; Signaling Protein; Site; Structural Biologist; Structure; Sulfamethoxazole; Surface; Synchrotrons; System; Technology; Temperature; Testing; Therapeutic; Time; Training; Visualization; Work; X ray diffraction analysis; X-Ray Crystallography; base; beamline; chemical reaction; computerized data processing; design; detector; electric field; experimental study; improved; macromolecule; man; movie; mutant; new technology; novel; novel strategies; open source; physical model; practical application; protein function; response; technology research and development; time use; transmission process; voltage

Abstract A major goal is biomedical science is to move beyond static images of proteins and other biological macromolecules to the internal dynamics underlying their function. This level of study is necessary to understand how these molecules work, to engineer new functions, and to rationally develop therapeutics. In this application, we propose two technological research and development projects that take advantage of the special characteristics of the BioCARS national synchrotron facility to address these goals. In the first, TR&D 1, we describe time-resolved serial micro-crystallography (TR-SMX) coupled with initiation of chemical reactions within molecules. This approach is enabled by the high intensity and tight focusing of X-rays at BioCARS, the availability of a large area, fast detectors, and the use of novel crystal injectors and microfluidic mixers. TR- SMX enables users to observe the dynamics of molecules as they execute their biological function at physiological temperatures. In the second, TR&D 2, we describe electric field-stimulated X-ray crystallography (EFX), a new method visualizing conformational changes within proteins and other biological macromolecules. This method uses external electric fields to induce global, subtle motions of atoms within proteins, with readout using time-resolved X-ray diffraction. Initial work demonstrates the practical application of EFX, and confirms the ability to globally excite motions throughout a protein molecule, including those of biological relevance. Since charges and dipoles are universally present in macromolecules, EFX represents, in principle, a general approach for intramolecular dynamics. We describe several user-based driving biomedical projects and collaborative and service projects that cover a wide range of important problems and push both technologies. User training and active approaches to dissemination to both expert and non-expert, wider audiences will enable broad use of the new technologies by the scientific community.

摘要 生物医学科学的一个主要目标是超越蛋白质和其他生物的静态图像 大分子与其功能背后的内部动力学有关。这一水平的学习对于 了解这些分子是如何工作的，设计新的功能，并合理地开发治疗方法。在……里面 在这个应用中，我们提出了两个技术研发项目，这两个项目利用 为了实现这些目标，BioCARS国家同步加速器设施具有独特的特点。在第一个，研发1， 我们描述了时间分辨序列微晶学(tr-smx)与化学反应的启动。 在分子内。这种方法是由BioCARS的高强度和紧密聚焦的X射线实现的， 大面积、快速探测器的可用性，以及新型晶体注射器和微流控混合器的使用。Tr- SMX使用户能够在执行其生物功能时观察分子的动力学 生理温度。在第二章，tr&d2中，我们描述了电场激发X射线结晶学 (EFX)，一种可视化蛋白质和其他生物大分子构象变化的新方法。 这种方法使用外加电场来诱导蛋白质内部原子的整体微妙运动，并读出 采用时间分辨X射线衍射法。初步工作演示了EFX的实际应用，并证实了 在整个蛋白质分子中整体激发运动的能力，包括那些与生物相关的运动。 由于电荷和偶极普遍存在于大分子中，因此EFX在原则上代表了一种 分子内动力学方法。我们描述了几个基于用户的驱动型生物医学项目 合作和服务项目，涵盖广泛的重要问题，并推动这两种技术。 用户培训和向专家和非专家、更广泛受众传播的积极方法将 使科学界能够广泛使用新技术。