CAREER: The Interaction of Ions with DNA: An X-ray Scattering Study

生命中最重要的两种分子，DNA和RNA，都是均匀带负电荷的。大自然利用带电粒子之间的强相互作用（例如，具有相反电荷的粒子之间的强吸引力或具有相似电荷的粒子之间的排斥）来控制这些核酸的形状和功能。这个研究项目使用x射线散射，一种新证明的实验技术，来解决关于带正电的反离子与带负电的核酸相互作用的基本问题。为了在溶液中保持电中性，DNA与带正电的伙伴结合，从小离子到大蛋白质。许多生物过程，包括基因调控和DNA修复，都是由DNA与带电分子的相互作用所调节的。这些强烈的相互作用也被用于药物的设计，靶向和修饰DNA的小分子。dna -电荷相互作用的重要性为这些系统性质的基础研究提供了强大的动力。这个实验项目的目的是利用模型DNA系统来探测这些相互作用。这项工作建立在最近在康奈尔高能同步加速器源进行的实验基础上，该实验使用异常小角度x射线散射来区分多组分系统（例如RbCl溶液中的DNA）中单个离子（例如Rb反离子）与所有其他原子/离子的散射特征。这些初步的测量使得对这些反离子在DNA周围的空间分布进行前所未有的定量测量成为可能。该项目将提供新的数据，以严格测试相关相互作用的相互冲突的理论模型。该项目的长期目标是利用这项新技术来解决与生物学相关的问题，例如带电配体在促进DNA链之间吸引力方面的作用。这种吸引力对我们理解DNA是如何包装和储存在细胞中的至关重要。更广泛的影响：这项工作将在一些领域产生影响，这些领域通过向广泛受众推广跨学科工作的主题联系在一起。这些活动的范围从参与K-12的外展，到开发一个项目，建立一个从以女性为主的本科院校到应用物理研究生项目的管道。这一管道项目的成功试点版本将作为未来努力的典范。此外，还将为康奈尔大学的本科生开设工程配送课程。本课程着重于跨学科科学，向工程和物理科学专业的学生介绍分子生物学中重要的、当前的主题。本课程将通过引入三个新模块将研究与教育相结合。这些模块的灵感来自于拟议的研究项目，并利用了康奈尔大学独特的研究设施。

Two of the most important molecules of life, DNA and RNA, are uniformly negatively charged. Nature takes advantage of the strong interactions between charged particles (e.g., the strong attraction of particles with opposite charges or repulsion of the ones with like charges), to control the shape and function of these nucleic acids. This research project uses x-ray scattering, a newly demonstrated experimental technique, to address fundamental questions about the interaction of positively charged counter-ions with negatively charged nucleic acids. To maintain electrical neutrality in solution, DNA is associated with positively charged partners ranging from small ions to large proteins. Numerous biological processes, including gene regulation and DNA repair, are regulated by the interactions of DNA with charged molecules. These strong interactions are also exploited in the design of pharmaceuticals, small molecules that target and modify DNA. This importance of DNA-charge interactions provides strong motivation for fundamental studies of the properties of these systems. This experimental project is designed to probe these interactions using model DNA systems. This work builds on recent experiments performed at the Cornell High Energy Synchrotron Source in which anomalous small angle x-ray scattering was used to distinguish the scattering signature of a single ionic species (e.g. Rb counterions) from all other atoms/ions in a multi-component system (e.g. DNA in a solution of RbCl). These preliminary measurements enabled unprecedented, quantitative measurements of the spatial distributions of these counterions around the DNA. This project will provide new data to rigorously test conflicting theoretical models of the pertinent interactions. The long-term goal of this project is to exploit this new technology to address biologically relevant questions, such as the role of charged ligands in facilitating attractive forces between DNA strands. This attraction is of fundamental importance to our understanding of how DNA is packaged and stored in our cells. Broader Impacts: This work will have impact in a number of arenas linked together by the theme of promoting interdisciplinary work to a wide audience. The activities range from participation in K-12 outreach through the development of a program to establish a pipeline from predominantly female undergraduate institutions to the Applied Physics graduate program. A successful pilot version of this pipeline program will serve as a model for future efforts. In addition, an Engineering Distribution course will be developed for Cornell undergraduates. The course focuses on interdisciplinary science by introducing important, current topics in molecular biology to students of engineering and physical sciences. Research and Education will be integrated through this course by introducing three new modules. These modules are inspired by the proposed research program and leverage on Cornell's unique research facilities.