Dynamics of intermolecular ion pairs at protein-DNA interfaces

蛋白质-DNA 界面分子间离子对的动力学

• 批准号: 1307344
• 负责人: Junji Iwahara
• 金额: $ 30万
• 依托单位: University of Texas Medical Branch at Galveston
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1307344&HistoricalAwards=false
• 关键词: Dynamics; intermolecular; ion; pairs; protein

With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Dr. Junji Iwahara of the University of Texas Medical Branch (UTMB)-Galveston to study the roles of the ion-pair dynamics in protein-DNA association. The work is collaborative with Dr. B. Montgomery Pettitt from UTMB-Galveston and Dr. David Gorenstein from UTHSC-Houston. The team will study the ion-pair dynamics for lysine and arginine side chains interacting with DNA phosphate groups in the HoxD9 homeodomain-DNA complex. The central hypothesis in this research project is that by allowing high mobility of involved atoms, the ion-pair dynamics are entropically important for protein-DNA interactions. The research team will test this hypothesis by using approaches of NMR spectroscopy, biophysical chemistry, organic chemistry, and computational chemistry. Three specific objectives to be pursued are: 1) characterizing the dynamics of intermolecular ion pairs between protein and DNA, 2) delineating motional changes of protein side-chain cations due to ion-pair formation with DNA, and 3) elucidating the mechanism by which oxygen-to-sulfur substitution in DNA phosphate enhances protein-DNA affinity. By providing the atomic-level information on the ion-pair dynamics at the biologically important macromolecular interfaces, this project will substantially deepen our understanding of ion pairs and their roles in protein function.Despite the universal importance of ion pairs in chemical and life sciences, dynamic properties of the ion pairs in life processes such as molecular recognition and catalysis are not well understood. This project aims to shed light on this fundamental problem, with a particular focus on ion pairs between protein and DNA. By unraveling the dynamics of these intermolecular ion pairs and their entropic effects on macromolecular association, this project is expected to facilitate the engineering of proteins and/or nucleic acids. The experimental data on the ion-pair dynamics for the relatively small protein-DNA complex will allow the computational chemistry community to validate and improve the molecular dynamics force fields. Moreover, in this project, research activities will be integrated into several educational/outreach activities. The PI will organize an NMR seminar series and a local NMR workshop for the Gulf Coast Consortium comprising scientists in the Greater Houston area. Results from this project are to be incorporated into an interdisciplinary course being developed by the PI, and outreach to high school students in the area is planned.

有了这个奖项，化学系的生命过程化学项目资助德克萨斯大学医学分支（UTMB）-加尔维斯顿的Junji Iwahara博士研究离子对动力学在蛋白质-DNA缔合中的作用。这项工作是与B博士合作进行的。来自UTMB-加尔维斯顿的蒙哥马利佩蒂特和来自UTHSC-休斯顿的大卫戈伦斯坦博士。 该团队将研究赖氨酸和精氨酸侧链与HoxD 9同源结构域-DNA复合物中DNA磷酸基团相互作用的离子对动力学。该研究项目的中心假设是，通过允许参与原子的高迁移率，离子对动力学对蛋白质-DNA相互作用具有熵重要性。研究小组将通过使用NMR光谱，生物物理化学，有机化学和计算化学的方法来验证这一假设。要追求的三个具体目标是：1）表征蛋白质和DNA之间的分子间离子对的动力学，2）描绘由于与DNA形成离子对而引起的蛋白质侧链阳离子的运动变化，以及3）阐明DNA磷酸中的氧到硫取代增强蛋白质-DNA亲和力的机制。通过提供原子水平上的离子对在生物重要的大分子界面上的动力学信息，该项目将大大加深我们对离子对及其在蛋白质功能中的作用的理解。尽管离子对在化学和生命科学中具有普遍的重要性，但离子对在分子识别和催化等生命过程中的动力学性质还没有得到很好的理解。该项目旨在阐明这一基本问题，特别关注蛋白质和DNA之间的离子对。通过揭示这些分子间离子对的动力学及其对大分子缔合的熵效应，该项目有望促进蛋白质和/或核酸的工程化。相对较小的蛋白质-DNA复合物的离子对动力学的实验数据将允许计算化学社区验证和改进分子动力学力场。此外，在本项目中，研究活动将被纳入若干教育/外联活动。 PI将组织一个NMR研讨会系列和一个当地的NMR研讨会，为墨西哥湾沿岸财团，包括科学家在大休斯顿地区。该项目的成果将被纳入公共研究所正在开发的跨学科课程，并计划向该地区的高中学生推广。