Sequence Specific Targeting of RNA Using Complementary Strands: Energetics, Kinetics and Hydration

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Ribonucleic acid (RNA) is known to play a central role in a wide variety of cellular processes. To exert their function, RNA molecules must fold into a specific three-dimensional structure. In this project, the PI and his students will study the folding energetics and hydration properties of complex RNA structures and will determine the thermodynamics and kinetics governing their association with complementary strands. This would help improve our current understanding of the physical factors that determine their stability, melting behavior and structure, which are basic to the rational design of targeting strategies and computational models. Furthermore, the data obtained in this project will be compiled on a free-to-access website and applied to molecular modeling of RNA structures to show that detailed thermodynamics is needed to bring RNA modeling to the same accuracy as DNA modeling. This project will have societal impacts in the mentoring of young scientists, including high school, undergraduate and graduate students, and postdoctoral fellows. The project will develop biophysical methods and will train students in a wide variety of biophysical techniques, exposing them to a diverse range of topics in the physical sciences. The PI incorporates the research findings into curricular enrichment and seminar presentations. The student presentations of their work at scientific conferences allow them to integrate within the scientific community. Furthermore, the PI recruits students from diverse groups to participate in the Summer undergraduate research program at his institution, co-organizes a educational workshop every other year in "Structural Biology and Molecular Biophysics" in the Midwest; and attends the annual SACNAS meeting to increase the participation of young scientists from diverse groups into biophysics. The PI's laboratory will obtain nearest-neighbor data on intramolecular RNA secondary structures and use this data to improve structural modeling and targeting of RNA. In particular, the project aims to determine the unfolding thermodynamics of RNA stem-loop motifs, pseudoknots, stem-loop motifs with bulges, three and four way junctions, and biologically relevant RNA riboswitches, such as preQ1, SAM-II, and adenine riboswitch, as a function of sequence, loop length and solution conditions. The thermodynamic results will be correlated with hydration and SAXS structural data. The PI will also study the thermodynamic contributions and kinetic rates governing the reaction of intramolecular RNA structures with their partially complementary strands (SS) via duplex formation and the molecular forces governing the formation of SS-polycation complexes and to use SS-polycation complexes for targeting RNA 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.