RNA is a molecular machine that carries out a large number of tasks within the cell. The awareness of its central involvement in biological processes is among the most remarkable scientific discoveries of the last thirty years. In the earliest models, RNA's role was relegated to that of messenger, passively copying and transporting pieces of the genetic code. Recent research illustrates its active participation in executing the instructions present in the genome. RNA's widely-varying functions range from 'splicing'genes together to regulating the concentrations of key metabolites. Many of these newly discovered roles rely on RNA folding to specific functional structures and responding to the environment by dynamically changing shape. The goal of this proposal is to obtain an atomically detailed picture of the RNA folding process. This vision is beyond current experimental capabilities, but is on the horizon for new simulation methods. However, simulation must be validated by observation. This project identifies important landmarks along the folding pathway of a small RNA that can be detected with advanced experimental tools. Observation of the time scale for and sequences of events will be determined by experiment, and used to validate simulations, which provide insight into atomically detailed processes. The expanding appreciation of RNA's biological roles brings recognition of its potential as a new target for drugs. Insights gained int the atomic level workings of RNA folding and dynamics may assist with RNA based drug design.

Public Health Relevance

The need for new antibiotics cannot be overstated as bacteria continue to acquire antibiotic resistance. Efforts are intensifying to develop drugs that specifically target bacterial RNAs. However, a lack of detailed understanding regarding small molecule binding by RNA limits drug development and will be facilitated by insights gained here into atomically detailed motions of RNA.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM085062-05A1
Application #
8656881
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Preusch, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Chen, Yujie; Tokuda, Joshua M; Topping, Traci et al. (2014) Revealing transient structures of nucleosomes as DNA unwinds. Nucleic Acids Res 42:8767-76
Meisburger, Steve P; Warkentin, Matthew; Chen, Huimin et al. (2013) Breaking the radiation damage limit with Cryo-SAXS. Biophys J 104:227-36
Meisburger, Steve P; Sutton, Julie L; Chen, Huimin et al. (2013) Polyelectrolyte properties of single stranded DNA measured using SAXS and single-molecule FRET: Beyond the wormlike chain model. Biopolymers 99:1032-45
Pabit, Suzette A; Sutton, Julie L; Chen, Huimin et al. (2013) Role of ion valence in the submillisecond collapse and folding of a small RNA domain. Biochemistry 52:1539-46
Chen, Huimin; Meisburger, Steve P; Pabit, Suzette A et al. (2012) Ionic strength-dependent persistence lengths of single-stranded RNA and DNA. Proc Natl Acad Sci U S A 109:799-804
Kirmizialtin, Serdal; Pabit, Suzette A; Meisburger, Steve P et al. (2012) RNA and its ionic cloud: solution scattering experiments and atomically detailed simulations. Biophys J 102:819-28
Kirmizialtin, Serdal; Silalahi, Alexander R J; Elber, Ron et al. (2012) The ionic atmosphere around A-RNA: Poisson-Boltzmann and molecular dynamics simulations. Biophys J 102:829-38
Li, Li; Pabit, Suzette A; Meisburger, Steve P et al. (2011) Double-stranded RNA resists condensation. Phys Rev Lett 106:108101
Blose, Joshua M; Pabit, Suzette A; Meisburger, Steve P et al. (2011) Effects of a protecting osmolyte on the ion atmosphere surrounding DNA duplexes. Biochemistry 50:8540-7
Pollack, Lois (2011) SAXS studies of ion-nucleic acid interactions. Annu Rev Biophys 40:225-42

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