Rapid screening of biomolecular conformation and binding interactions

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，这将使成像生物大分子（例如DNA， RNA，蛋白质）的纳米级构象成为可能，其尺寸比目前可以探测的要小得多。这个平台将是健壮的，并适应自动化。该项目将提供支持高通量筛选具有先进化学和生化功能的化合物所需的创新能力（例如，治疗靶点）。项目方法对可检测的大分子的大小没有限制，并且可以在10到20分钟的实验内完成，使吞吐量比目前可能的高几个数量级。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格式，使普通观众能够以一种有趣而引人入胜的方式访问纳米级物理并与之互动，就像熟悉的平板电脑游戏一样。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（例如DNA， RNA，蛋白质）的构象变化，包括自诱导的和由结合剂（例如小分子，蛋白质，加合物）络合产生的构象变化。一系列基于小分子和蛋白质的结合物种将被评估，包括不同的结合模式，以量化它们对大分子构象的影响。还将开发一个预测模型，为合理选择量身定制的纳米多孔水凝胶配方和聚合条件提供信息，从而在广泛的分析物尺寸范围内对大分子构象进行最佳探测。这项工作将为建立一种新的工具奠定基础，该工具能够以一种高度自动化的方式对结合相互作用进行快速并行筛选，这是现有方法无法实现的。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，提供聚合物线圈尺寸、松弛现象、布朗运动和外部驱动力（即电泳）下的传输的可视化表示。这款应用将利用流行电子游戏所使用的嵌入式2D物理引擎，使模拟工具箱易于使用，并且以一种仅通过呈现物理效果来实现的方式具有挑战性。最后，该项目将培训和指导一名博士生，并从STEM中代表性不足的群体中招募本科生和高中生进行研究经验。

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.