The Turner group is developing methods for rapidly determining structures of RNA and for identifying compounds for targeting RNA with therapeutics. The database of nucleic acid sequences is growing at a rate of over a million nucleotides a day. To maximize effective use of the sequence database, the Turner group is working on combining thermodynamic studies of folding stabilities of RNA motifs with sequence comparison and gel based structure mapping methods in order to deduce secondary structures. For example, in collaboration with Prof. Michael Zuker at the Rensselaer Polytechnic Institute, they have improved an algorithm for prediction of secondary structure from sequence so that predictions are now roughly 70% accurate on average for a single sequence of up to 500 nucleotides. This is currently the most popular algorithm for predicting RNA secondary structure. Structure predictions are also being used to identify attractive RNA targets and to design therapeutics targeting these RNAs, particularly in the human pathogen, Candida albicans.
Continuing progress in predicting secondary structure from sequence relies on development of a deeper understanding of the sequence dependence of folding stabilities of various RNA motifs. For example, internal loops have a wide variation of stabilities. Interpretation and generalization of these sequence effects requires knowledge of the three dimensional structures formed by selective sequences. NMR studies are beginning to provide this information. These structural studies will also provide the database necessary to start predicting 3D structure from sequence.
Mathews, D.H., Disney, M.D., Childs, J.L., Schroeder, S.J., Zuker, M., Turner, D.H. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc. Natl. Acad. Sci. USA 2004; 101: 7287-7292.
Chen, G., Znosko, B.M., Jiao, X., Turner, D.H. Factors affecting thermodynamic stabilities of RNA 3X3 internal loops. Biochemistry 2004; 43:12865-12876.
Childs JL, Disney MD, Turner DH. Oligonucleotide directed misfolding of RNA inhibits Canadida albicans group I intron splicing. Proc Natl Acad Sci USA 2002;99:11091-11096.