Rapid screening of biomolecular conformation and binding interactions

CBET 1605167 Ugaz，V.生物分子构象和结合相互作用的快速筛选这个基础研究项目将开发一种用于生物分离的新工具，该工具将使生物大分子（例如DNA，RNA，蛋白质）的纳米级构象的成像成为可能，其尺寸比目前可以探测的要小得多。这个平台将是强大的，并适合自动化。该项目将提供支持高通量筛选具有先进化学和生物化学功能的化合物所需的创新能力（例如，治疗目标）。该项目方法对可以被询问的大分子的大小没有下限，并且可以在10到20分钟的实验内进行，从而使吞吐量比目前可能的高出几个数量级。更广泛地说，使这种分析成为可能的基本物理基础将用于基于平板电脑的计算机格式，使普通观众能够以一种有趣和引人入胜的方式访问和互动纳米物理学，反映熟悉的平板电脑游戏。首席研究员将进行基础研究，旨在建立一种创新的熵力显微镜，能够定量绘制生物大分子的构象变化在一些实施方案中，结合剂（例如，DNA、RNA、蛋白质）可以是自诱导的，也可以是从与结合剂（例如，小分子、蛋白质、加合物）的复合中出现的。将评估一系列小分子和基于蛋白质的结合物质，包括不同的结合模式，以量化其对大分子构象的影响。还将开发预测模型，以告知定制的纳米多孔水凝胶配方和聚合条件的合理选择，使大分子构象能够在广泛的分析物尺寸范围内进行最佳探测。这项工作将奠定一个基础，建立一个新的工具，能够执行快速并行筛选的结合相互作用的高度自动化的方式不可能使用现有的方法。更广泛地说，传统的布朗动力学模拟工具箱将被实现到iPad应用程序中，该应用程序提供聚合物线圈尺寸、弛豫现象、布朗运动和在外部驱动力（即，电泳）。该应用程序将利用流行的视频游戏所使用的嵌入式2D物理引擎，使模拟工具箱可访问并以一种具有挑战性的方式参与，通过单独呈现物理来实现。最后，该项目将培养和指导一名博士。学生和本科生和高中生将从STEM中代表性不足的群体中招募研究经验。

CBET 1605167 Ugaz, V.Rapid screening of biomolecular conformation and binding interactionsThis fundamental research project will develop a new tool for biological separations that will make it possible to image the nanoscale conformation of biomacromolecules (e.g. DNA, RNA, proteins) much smaller in size than can currently be probed. This platform will be robust and amenable towards automation. This project will deliver innovative capabilities that are needed to support high throughput screening of compounds with advanced chemical and biochemical functions (e.g., therapeutic targets). The project approach imposes no lower limit on the size of macromolecules that can be interrogated and can be performed within a 10 to 20 minute experiment, enabling orders of magnitude higher throughput than currently possible. More broadly, the fundamental physical underpinnings that make this analysis possible will be used in a tablet-based computer format, enabling general audiences to access and to interact with nanoscale physics in a fun and engaging way that mirrors familiar tablet games.The principal investigator will conduct fundamental research that is aimed at establishing an innovative entropic force microscope capable of quantitatively mapping conformational changes in biomacromolecules (e.g. DNA, RNA, proteins), both self-induced and emerging from complexation with binding agents (e.g. small molecules, proteins, adducts). A slate of small molecule and protein-based binding species will be evaluated encompassing different binding modes to quantify their influence on macromolecular conformation. A predictive model will also be developed to inform the rational selection of tailored nanoporous hydrogel formulations and polymerization conditions, enabling macromolecular conformation to be optimally probed within a broad range of analyte size. This work will lay a foundation to establish a new tool capable of performing rapid parallel screening of binding interactions in a highly automated fashion not possible using existing methods. More broadly, a conventional Brownian dynamics simulation toolbox will be implemented into an iPad application that provides a visual representation of polymer coil size, relaxation phenomena, Brownian motion, and transport under an external driving force (i.e., electrophoresis). The app will harness the embedded 2D physics engine employed by popular video games, making the simulation toolbox accessible and engaging in a way that is challenging to achieve by presenting the physics alone. Finally, the project will train and mentor a Ph.D. student and undergraduate and senior high school students will be recruited from underrepresented groups in STEM for research experiences.