Fluorescent Nucleosides and Oligonucleotides with New Capabilities

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In this project, funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Byron Purse of San Diego State University is seeking to develop a deep understanding of the relationship between chemical structure, local molecular environment, and fluorescent properties of nucleobase analogues, synthetic building blocks for DNA and RNA. These fluorescent nucleobase analogues (FBAs) are an important class of molecular probes, used to understand the biochemical mechanisms that control gene expression and the maintenance and copying of the genetic code. Designing fluorescent molecular probes for these applications is challenging and the capabilities of FBAs are limited because it is not yet possible to predict how their fluorescence will change when the probes are placed in a biological context. Integral to this research is a plan to train graduate students who will lead the laboratory work and participate in all aspects project planning, data analysis, interpretation, collaborations, and the dissemination of results. The involvement of undergraduate researchers is included, as is a Course-based Undergraduate Research Experience (CURE) in the SDSU Physical Chemistry Lab to further broaden participation.This project has three specific technical objectives: (1) to develop fluorescent nucleobase analogues (FBAs) with high brightness and photostability and assess their performance in fluorescence studies of nucleic acids at the single-molecule level; (2) to develop the ability of pairs of FBAs to measure short and long-range structure and dynamics simultaneously using spectral feature analysis and FRET and (3) to develop a theoretical approach to understanding FBA photophysics and responses to local environment using a combination of new analogue design and synthesis, fluorescence studies, and computation. The research supported by this project seeks to measure and understand how fluorescence changes when FBAs are placed in differing contexts in DNA and RNA and use this understanding, together with synthetic organic chemistry, to create new fluorescent probes with enhanced capabilities to accelerate discovery.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.