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Next-Generation Fluorescent Nucleosides and Structure-Photophysics Relationships

下一代荧光核苷和结构-光物理关系

基本信息

批准号：
1800529
负责人：
Byron Purse
金额：
$ 41.42万
依托单位：
San Diego State University Foundation
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1800529&HistoricalAwards=false
关键词：
Next Generation Fluorescent Nucleosides Structure

项目摘要

In this project, funded by the Chemical Structure, Dynamics and Mechanisms B Program of the Chemistry Division, Professor Byron Purse of the Department of Chemistry and Biochemistry at San Diego State University (SDSU) is developing fluorescent nucleoside analogues as molecular probes with new capabilities for biophysical studies of nucleic acids. In addition to storing the genetic code, nucleic acids can undergo chemical modification, adopt folded structures, and interact with proteins and enzymes for the regulation of gene expression and metabolism. Fluorescent nucleoside analogues are powerful probes for studying these processes, but existing analogues have limited capabilities. Insufficient knowledge of the factors controlling their fluorescence hinders the rational design of better probes. This project seeks to overcome these limitations and expand the toolkit of fluorescent nucleoside analogue probes with significant, novel capabilities. The design of the new analogues is aided by detailed mechanistic studies of how the local environment in DNA/RNA influences the fluorescence of the probes. This cross-disciplinary research provides excellent training opportunities for students at multiple levels. In addition to graduate student and undergraduate involvement, a Course-based Undergraduate Research Experience (CURE) in the SDSU Physical Chemistry teaching lab and an outreach program involving computational work with community college and high school students will broaden participation in the research.Probably the greatest challenge in designing fluorescent probes that mimic the structure of biomolecules is that limited ability to predict photophysical properties currently necessitates a trial-and-error approach. In this project, photophysical measurements, computation, NMR, and x-ray structure determination are combined to develop a detailed, predictive understanding of the relationships between nucleoside analogue structure and photophysics, especially in the base stack of DNA and RNA. By harnessing these trends and synthesizing new fluorescent nucleoside analogue designs, novel probes with (a) brightness matching conventional fluorophores, (b) absorption and emission at the red end of the visible spectrum, (c) strong fluorescence turn-on responses to specific biomolecular recognition events, and (d) the ability to report on chemical modifications to nucleobases, e.g. from methylation or DNA damage are being developed.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在该项目中，由化学部化学结构、动力学和机制B计划资助，圣地亚哥州立大学（SDSU）化学和生物化学系的Byron Purse教授正在开发荧光核苷类似物作为具有核酸生物物理研究新能力的分子探针。除了储存遗传密码外，核酸还可以进行化学修饰，采用折叠结构，并与蛋白质和酶相互作用以调节基因表达和代谢。荧光核苷类似物是研究这些过程的强有力的探针，但现有的类似物具有有限的能力。控制其荧光的因素的知识不足，阻碍了更好的探针的合理设计。该项目旨在克服这些局限性，并扩大具有显著新颖能力的荧光核苷类似物探针的工具包。新类似物的设计是通过详细的机制研究DNA/RNA中的局部环境如何影响探针的荧光来辅助的。这种跨学科的研究为学生提供了良好的培训机会，在多个层次。除了研究生和本科生的参与，基于课程的本科生研究体验（CURE）在SDSU物理化学教学实验室和一个涉及社区大学和高中学生计算工作的外展计划将扩大研究的参与。设计模拟生物分子结构的荧光探针的最大挑战可能是目前预测生物物理性质的能力有限。需要反复试验在这个项目中，结合了核物理测量，计算，NMR和X射线结构测定，以发展对核苷类似物结构和核物理之间关系的详细的，预测性的理解，特别是在DNA和RNA的碱基堆叠中。通过利用这些趋势并合成新的荧光核苷类似物设计，新型探针具有（a）与常规荧光团匹配的亮度，（B）在可见光谱的红端的吸收和发射，（c）对特定生物分子识别事件的强荧光开启响应，和（d）报告对核碱基的化学修饰的能力，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。