Chemistry & Biochemistry

General

• Assistant Professor
• B.S., University of Rochester, 1995
• Ph.D., University of Rochester, 2002
• Postdoctoral Fellow, Yale University, 2002-2005
• Ruth L. Kirschstein National Research Service Award Individual Fellowship, 2003-2005

Research

• RNA structure, function, and energetics; RNA structure prediction; viral RNA

Research Description

My long-term goal is to predict the three dimensional structure of ribonucleic acids (RNA).� RNA plays important roles in the processing, regulation, and transformation of genetic information in cells.� RNA folds into three-dimensional structures and thus achieves specificity in molecular recognition and enzymatic activity.� My research will probe the structure and energetics of viral RNAs and initially focus on: (1) the RNA structure in satellite tobacco mosaic virus, (2) the ATP-binding motif in phi29 packaging RNA, and (3) thermodynamic stabilities of motifs in RNA interference phenomena.� Information from a variety of experiments including, UV optical melting, NMR, crystallography, chemical probing, as well as standard molecular biology and biochemistry techniques, will be required to solve these problems.� The lessons learned from solving these challenging problems will contribute to understanding the fundamental interactions that determine RNA structure and function and thus lead to better RNA structure predictions.�

Science (1989) 243, p.786
www.chasetoons.com

We finished the genome map, now we can't figure out how to fold it!

Genome sequencing projects and the rapid advances in nucleic acid sequencing technology provide abundant sequence (primary structure) information.� The challenge remains how to use this information to understand the structure and function of RNA and protein molecules encoded within the genome sequence.� Both RNA and proteins are biological polymers with non-random sequences of nucleotides and amino acids. The sequence of nucleotides or amino acids determines the structure of the molecule and thus also the function of the molecule. A folding funnel, like the one shown below, describes the folding of biological polymers to the lowest free energy conformation.

RNA Folding Problem


Figure from Dill &Chan (1997) Nat. Struct. Biol. Vol. 4, pp. 10-19

The Watson-Crick base pairs in RNA form helices and thus the secondary structure of the RNA.� Non-base-paired regions such as internal loops, bulges, and hairpin loops are the junctions between the RNA helices.� The thermodynamic stability of RNA helices makes the RNA folding process hierarchical.� The secondary structure forms first and then the RNA helices are arranged in an overall three-dimensional structure.� The figure below shows the primary structure (sequence), secondary structure (RNA helices and non-helical regions), and tertiary structure of the P4-P6 domain of a group I intron, which is an RNA enzyme.� The hierarchical nature of RNA folding makes the RNA folding problem tractable, and much progress has been made in predicting RNA secondary structure from sequence.� Predicting RNA three-dimensional structures remains challenging.

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The figure below shows a model of the satellite tobacco mosaic virus icosahedral particle with the RNA helices shown as green tubes. �The identity of the bases in the helices has been obscured by the icosahedral averaging done to solve the crystal structure; and the nonhelical RNA is also icosahedrally disordered.� Thus, STMV presents a novel RNA folding problem.� The minimum number of helices, the minimum length of the helices, the relative orientation of the helices to each other and to the protein shell, the total volume and overall shape of the RNA, and the icosahedral symmetry provide powerful restraints for RNA structure prediction.� The RNA sequence itself shows no repetitive patterns but holds the secret to the RNA structure.

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