Daniel Herschlag

Ph.D., Brandeis, 1988.
Professor of Biochemistry

Email:
Web: http://cmgm.stanford.edu/biochem/herschlag/

For RNA folding we would like to understand how a random polymer with considerable freedom of motion and little internal communication collapses to form a specific, highly interconnected, cooperative structure. To accomplish this we focus on folding of the Tetrahymena thermophila group I self-splicing intron, a complex functional RNA, studying the intact ribozyme, fragments thereof, and smaller model RNAs. Comparisons of RNA and protein folding, as well as catalysis (below), help elucidate unique features of these different classes of functional biomolecules through differences in their behavior; commonalities suggest features that may be fundamental to the adoption of specific structures and biological function. We use a multidisciplinary approach to study both RNA folding and protein and RNA catalysis, spanning from kinetic and thermodynamic dissection of pathways and processes, to chemical synthesis to facilitate comparative studies, to many biophysical techniques including single molecule fluorescence and force spectroscopy, solution small angle x-ray scattering, fluorescence lifetime and anisotropy, NMR, EPR, and x-ray crystallography, to computational approaches to help model and understand experimental results. In biological catalysis, we are fascinated with the enormous rate enhancements and exquisite specificity of enzymes, both RNA and protein. We are studying the RNA enzyme or ribozyme derived from the self-splicing group I intron from Tetrahymena. The goals are to learn more about RNA catalysis &endash;an apparently ancient and still-functional class of enzymes, and to general principles of biological catalysis. Protein enzymes currently under investigation include E. coli alkaline phosphatase and bacterial ketosteroid isomerase, enzymes chosen because they are easily manipulated, because multiple structure-function approaches can be taken, and because questions fundamental to catalysis can be posed. Thesestudies are complemented by nonenzymatic investigations of the underlying chemical mechanisms, hydrogen bond energetics, and entropic barriers to reaction.

Select Publications (2004 - present)

Zalatan JG, Herschlag D (2006). "Alkaline phosphatase mono- and diesterase reactions: comparative transition state analysis." J Am Chem Soc 128: 4: 1293-303.

Arava Y, Boas FE, Brown PO, Herschlag D (2005). "Dissecting eukaryotic translation and its control by ribosome density mapping." Nucleic Acids Res 33(8): 2421-32.

Forconi M, Herschlag D (2005). "Promiscuous catalysis by the tetrahymena group I ribozyme." J Am Chem Soc 127(17): 6160-1.

Das R, Laederach A, Pearlman SM, Herschlag D, Altman RB (2005). "SAFA: semi-automated footprinting analysis software for high-throughput quantification of nucleic acid footprinting experiments." RNA 11(3): 344-54.

Bai Y, Das R, Millett IS, Herschlag D, Doniach S (2005). "Probing counterion modulated repulsion and attraction between nucleic acid duplexes in solution." Proc Natl Acad Sci U S A 102(4): 1035-40.

Nikolic-Hughes I, O'brien PJ, Herschlag D (2005). "Alkaline Phosphatase Catalysis Is Ultrasensitive to Charge Sequestered between the Active Site Zinc Ions." J Am Chem Soc 127(26): 9314-5.

Das R, Travers KJ, Bai Y, Herschlag D (2005). "Determining the Mg2+ stoichiometry for folding an RNA metal ion core." J Am Chem Soc 127(23): 8272-3.

Gerber, A. P., Herschlag, D. and Brown, P. O. (2004) "Extensive Association of Functionally and Cytotopically Related mRNAs with Puf-family RNA-binding Proteins in Yeast." PLoS Biology. 2(3), 0342-0354.

Nikolic-Hughes, I., Rees, D. C., Herschlag, D. (2004) "Do Electrostatic Interactions with Positively Charged Active Site Groups Tighten the Transition State for Enzymatic Phosphoryl Transfer?" J. Am. Chem. Soc. 126(38):11814-11819.

Takamoto, K., Das, R., He, Q., Doniach, S., Brenowitz, M., Herschlag, D., Chance, M. (2004)  "Principles of RNA compaction:  Insights From the Equilibrium Folding Pathway of the P4-P6 RNA Domain in Monovalent Cations." J. Mol. Biol. 343: 1195-1206.

Karbstein, K., Tang, K-H., Herschlag, D. (2004) "A Base Triple in the Tetrahymena Group I Core Affects the Reaction Equilibrium via a Threshold Effect". RNA 10:1730-1739.

Andresen, K., Das, R., Park, H. Y., Smith, H., Kwok, L. W., Lamb, J. S., Kirkland, E. J., Herschlag, D., Finkelstein, K. D., Pollack, L. (2004) "Spatial Distribution of Competing Ions Around DNA in Solution". Physical Review Letters  93:248013-1 -248103-4.

Last Updated: 2/23/06