Electric Field-stimulated Protein Mechanics

电场刺激的蛋白质力学

基本信息

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
项目类别：
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

项目摘要

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.

抽象的生物医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及其功能背后的内部动力学。这个级别的学习是必要的了解这些分子如何工作，设计新功能，并合理开发治疗方法。在在此应用中，我们提出了两个技术研发项目，利用 BioCARS 国家同步加速器设施的特殊特征可以实现这些目标。在第一个 TR&D 1 中，我们描述了时间分辨串行微晶体学 (TR-SMX) 与化学反应的引发分子内。这种方法是通过 BioCARS 的 X 射线的高强度和紧密聚焦来实现的，BioCARS 是大面积、快速检测器的可用性以及新型晶体注射器和微流体混合器的使用。 TR- SMX 使用户能够观察分子在执行其生物功能时的动态生理温度。在第二篇 TR&D 2 中，我们描述了电场激励 X 射线晶体学（EFX），一种可视化蛋白质和其他生物大分子内构象变化的新方法。该方法使用外部电场来诱导蛋白质内原子的整体、微妙的运动，并具有读数使用时间分辨X射线衍射。初步工作展示了 EFX 的实际应用，并证实了全局激发整个蛋白质分子运动的能力，包括那些具有生物相关性的运动。由于电荷和偶极子普遍存在于大分子中，因此 EFX 原则上代表了一般分子内动力学方法。我们描述了几个基于用户的驱动生物医学项目和涵盖广泛重要问题并推动这两种技术发展的协作和服务项目。用户培训和向专家和非专家、更广泛的受众传播的积极方法将使科学界能够广泛使用新技术。