Anne M. Baranger
Associate Professor of Chemistry
Anne Baranger attended the Massachusetts Institute of Technology where she did research with Professor Stephen L. Buchwald. After receiving her B.S. in chemistry in 1988, she did graduate work at the University of California, Berkeley. Working with Professor Robert G. Bergman, she studied a catalytic synthesis of enamines and the synthesis and reactivity of an early-late heterobimetallic bridging imido complex. Awarded a Ph.D. in chemistry in 1993, she became a postdoctoral fellow at Yale University with Professor Alanna Schepartz, investigating the molecular mechanism of the interaction of the human T-cell leukemia viral protein Tax with a class of cellular transcription factors. Professor Baranger joined the Wesleyan University faculty in 1996 and the the University of Illinois chemistry faculty in July 2006.
My group uses chemical approaches to address biological problems. In particular, we are interested in understanding, controlling, and modifying processes involving RNA. This is an exciting time to be working on RNA as many important, new biological roles of RNA have been discovered in only the last few years, including RNA interference, micro RNA, RNA switches, while many more probably remain to be discovered. These discoveries present a unique opportunity for chemists to contribute to the development of an understanding of these processes and to develop methods to control them. We follow a wide range of approaches to tackle the projects outlined below. Thus, a student graduating from my group gains an interdisciplinary background while acquiring expertise in specific areas of their choosing. There are four main projects in my group:
I. Bioorganic basis of RNA-protein recognition
This project focuses on understanding the molecular interactions responsible for the stability and specificity of complexes formed between RNA and proteins containing the RRM motif. The RRM is one of the most common RNA binding domains and is involved in most steps of gene expression in eukaryotes. Using the U1A-RNA complex as a model system, we have identified amino acids that are essential to high binding affinity, have delineated networks of cooperative interactions that influence binding by affecting the stability of either the free protein or the complex, and have shown that improving stacking interactions can compensate for the loss of hydrogen bonding functional groups known to contribute to binding affinity. We are probing the generality of these conclusions by investigating other RRM-RNA complexes.
One of the most interesting, yet unexplored, areas of RNA-protein recognition involves induced fit and dynamic processes. The importance of induced fit and dynamic processes in the formation of biological complexes is clear, but quantifying the contributions of these processes to affinity and specificity is difficult. We are combining NMR, time-resolved fluorescence, and theoretical methods to address this important problem in RRM-RNA complexes. Initial results suggest that correlated motions throughout the protein track with the energetic cooperation between residues that is observed in binding studies. Thus, investigation of the dynamics of this system may lead to an understanding of the basis for energetically coupled interactions.
II. Recognition of non-helical RNA structures by peptides and small molecules.
This project focuses on discovering sets of structurally diverse ligands for stable, structured non-helical RNA that are biologically important targets. Small molecules or peptides able to bind specific RNA structures or sequences could be valuable tools for investigating and controlling the many essential biological processes that involve RNA. We are taking two approaches to ligand discovery. First, we are using phage display methods to create libraries of peptides biased towards binding RNA stem loops. We anticipate that these peptides will be powerful tools for the selective perturbation of numerous biological processes involving RNA and will help develop principles for the recognition of proteins by RNA. Second, we are using computational docking to identify small molecules that bind to different RNA structures. We have identified two molecules that bind selectively to different non-helical RNA structures, an RNA tetraloop and an overhang structure. We are elaborating the core structures of these molecules to improve affinity and specificity and contribute to a fundamental understanding of the recognition of non-helical RNA structures. We also continue to conduct computational searches of small molecule databases for new molecular scaffolds that bind RNA.
III. Design of RNA-protein complexes using the RRM domain.
We are using our developing understanding of the ability of the RRM to act as a general single-stranded RNA-binding scaffold to develop new proteins that could bind RNA in a manner that would allow us to control biological function. We plan to develop proteins that could bind to particular RNA sequences, using a combination of selection techniques and rational design. With these unnatural RRMs we would conduct studies that would control RNA modification processes, such as splicing and polyadenylation that are often aberrant in human diseases including cancer.
IV. Small molecule control of RNA-protein complexes
We are using several approaches to develop small molecules that we can use to control the formation or dissociation of RNA-protein complexes. Combining these small molecules with the designed RRMs discussed above, one can envision activating an unnatural RRM by associating two fragments or inducing a change in conformation with a small molecule. With such systems we could control RNA processing events, including RNA splicing, investigate the temporal and spatial control of these processes, and develop pharmacological agents for controlling these processes.
Ong, H.C.; Arambula, J.F.; Ramisetty, S.R.; Baranger, A.M.; Zimmerman, S.C. "Molecular Recognition of a Thymine Bulge by a High Affinity, Deazaguanine-based (DAD) Hydrogen Bonding Ligand", Chem Comm., 2009, advance article
Zhao, Y.; Knee, J.L.; Baranger, A.M. "Characterization of Two Adenosine Analogs as Fluorescence Probes in RNA" Bioorg. Chem., 2008, 36, 271-277
Anunciado, D.; Agumeh, M.; Kormos, B.L.; Beveridge, D.L.; Knee, J.L.; Baranger, A.M. "Characterization of the Dynamics of an Essential Helix in the U1A Protein by Time-Resolved Fluorescence Measurements", J. Phys. Chem. B., 2008, 112, 6122-6130
Benitex, Y.; Baranger, A.M. "Recognition of Essential Purines by the U1A Protein", BMC Biochemistry, 2007, 8:22
Yan, Z.; Ramisetty, S.R.; Bolton, P.H.; Baranger, A.M. "Selective Recognition of RNA Helices Containing Dangling Ends by a Quinoline Derivative" ChemBioChem, 2007, 8, 1658.
Yan, Z.; Sikri, S.: Beveridge, D.L.; Baranger, A.M. "Identification of an Aminoacridine Derivative that Binds to RNA Tetraloops" J. Med. Chem., 2007, 50, 4096-4104.
Kormos, B.L.; Benitex, Y.; Baranger, A.M.; Beveridge, D.L. "Affinity and Specificity of Protein U1A-RNA Complex Formation Based on an Additive Component Free Energy Model" J. Mol. Biol., 2007, Vol. 371. Issue 5, 1405-1419.
Kormos, B.L; Baranger, A.M.; Beveridge, D.L. "A Study of Collective Atomic Fluctuations and Cooperativity in a U1A-RNA Complex Based on Molecular Dynamics Simulations" J. Struct. Biol., 2007, 157, 500.
- Alfred P. Sloan Research Fellowship, 2002-2004
- Donaghue Foundation Postdoctoral Fellowship, 1995
- Rudolph Anderson Postdoctoral Fellowship, Yale University, 1993-95
- Dr. Baranger and Dr. Steven C. Zimmerman have designed a small molecule that blocks an aberrant pathway associated with myotonic dystrophy type 1, the most common form of muscular dystrophy. Their research has been highlighted by the UIUC News Bureau, Science Daily, e!Science News, United Press International, and many more.