Chiral sum frequency generation spectroscopy for characterization of DNA secondary structures

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DNA has a signature structure of a double helix and the well-known function of storing genetic information. However, recent studies have revealed that DNA can adopt conformations other than that of a double helix, and DNA in these conformations can participate in the signaling process to regulate gene expression, and thereby direct cellular processes for survival of biological systems. The Chemistry of Life Processes Program in the Division of Chemistry is funding Dr. Elsa Yan from Yale University to develop a new method for distinguishing various conformations of DNA, which is named chiral sum frequency generation spectroscopy. This method has advantages over existing methods, such as NMR spectroscopy, X-ray crystallography, and linear optical spectroscopy, because it has high selectivity and low background, and it allows the real-time detection of small amounts of DNA. Given these advantages, the method may improve our ability to formulate rules involving various DNA conformations for forecasting biological behavior in response to changes in environment (e.g., injury and infections) or needs of cellular development (e.g., aging and cell splitting). The project also includes education activities meant to promote inclusive learning at Yale University, where the student body has become increasingly diverse. Pedagogical strategies seeking to help under-represented minority students to succeed are implemented in a chemistry course for non-science majors; their effectiveness is assessed by education experts. The project also includes participation in a science outreach program for local grade-school students that aims to spark student interest in chemistry and the sciences in general. The project seeks to use chiral vibrational sum frequency generation spectroscopy to identify vibrational signatures that can be used to unambiguously resolve various DNA secondary structures. The project focuses on DNA secondary structures that are implicated in the regulation of gene expression, such as G-quadruplexes and i-motifs. The vibrational signatures are then used to examine the relationship between DNA secondary structures and chemical modifications. The project examines how the oxidation of nucleobases in various DNA sequences and configurations perturb the secondary structure of the DNA. The results are used to evaluate the impact of DNA oxidative damage on gene expression and function. The project is expected to establish a new method for characterizing DNA secondary structures and improve our understanding of how DNA regulates gene expression through the mechanism of changes in DNA secondary structures.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.