Co-Investigator: Michael Zuker

Professor, Mathematical Sciences and Biotechnology, Rensselaer Polytechnic Institute

Dr. Zuker works on the development of algorithms to predict nucleic acid folding and hybridization by free energy minimization using empirically derived thermodynamic parameters. Modeling and algorithm development have been closely coupled with the derivation of "nearest neighbor" and related energy rules in the laboratories of D. H. Turner, (RNA parameters, Department of Chemistry, University of Rochester, Rochester, NY) and of J. SantaLucia (DNA parameters, Department of Chemistry, Wayne State University, Detroit, MI).

Current work is focused on the computation of partition functions for systems containing two molecules in solution that can fold as well as hybridize with each other. Ensemble free energies, mole fractions of different monomer and dimer species and base pair probabilities are computed over a range of temperatures. These computations lead to the prediction of UV absorbance (optical density) and heat capacity (Cp) melting profiles that can be directly compared with experimental data. Closely related to this work is the development of an algorithm named "FASTH" that searches RNA or DNA sequence databases for optimal hybridization sites for nucleic acid query sequences. Unlike traditional search algorithms, such as BLASTN and FASTA, "FASTH" uses hybridization free energy as the criterion for selection.

Applications:

Dr. Zuker's well-known RNA folding software has proved useful in computing a number of sec- ondary structures that can experimentally tested for validity. Predicted foldings can be constrained by the incorporation of (experimentally determined) constraints. Such computations have been used to identify functionally important regions of single-stranded RNA viruses or conserved structures in 30UTR regions of mRNAs that function as controls for the spacial and temporal expression of certain genes.

The database searching, hybridization and melting profile computations have important applica- tions in biotechnology, where they can be used to design, for example, ecient gene specific probes, PCR primers or molecular beacons. Molecular beacons are used to identify SNPs (Single Nucleotide Polymorphisms) in DNA.

The FASTH algorithm is also useful in identifying putative hybridization sites for small ncRNAs (non-coding RNAs), such as miRNAs (microRNAs), that regulate gene expression by binding to mR- NAs.

Dr. Zuker's software is widely used around the world and is also available to the scientific community on a web server supported, in part, by both RPI and IBM Research.