Graduate students in biochemistry and chemical biology meld molecular and structural biology with physical, organic and analytical chemistry to understand the molecular basis of biological processes and of human disease. Research in the Biochemistry and Chemical Biology Division focuses on the structure and function of proteins, membranes, DNA, RNA, large macromolecular complexes and viruses, natural product biogenesis, synthetic biology, and genomics.
Students are a constant source of new hypotheses for mechanisms underlying cellular machines like the ribosome and spliceosome, and for the protein and RNA folding problems. Students tackle these problems using biochemical methods, chemical biosensor technologies, protein and nucleic acid crystallography, in vitro and in vivo evolution, multi-dimensional NMR spectroscopy, surface chemistry, atomic force microscopy, fluorescence spectroscopy, and high-resolution mass spectrometry.
Doctoral students in Biochemistry and Chemical Biology leave the Department broadly trained for leadership roles in academia and industry.
A major challenge in understanding the structure of large RNAs — including the genomes of RNA viruses — is discovering where the functionally critical parts lie. One structure, called an RNA pseudoknot, tends to occur in key areas that affect viral replication and other activities and could make strong drug targets. However, pseudoknots are hard to predict in RNA secondary structures and existing modeling techniques are generally not able to detect them reliably.
In work published in the Proc. Natl. Acad. Sci. USA, Christine Hajdin in the Weeks lab melded experimental and computational techniques to identify pseudoknots with a high degree of accuracy. She initially applied her approach to a set of 21 challenging RNAs of up to 530 nucleotides in size. Christine's approach recovered 93% of known RNA base pairs and all pseudoknots in well-folded RNAs were identified. More recently, Christine's approach has been used to successfully predict functionally important pseudoknots, "golden RNA needles", in the HIV virus RNA genome "haystack."
Researchers in the Waters Group, as described in an article published in JACS, utilized dynamic combinatorial chemistry to identify a novel small molecule receptor, A2D, for asymmetric dimethyl arginine, aRMe2, which is a post-translational modification, PTM, in proteins. It is known to play a role in a number of diseases, including spinal muscular atrophy, leukemia, lymphoma, and breast cancer.
The receptor exhibits 2.5–7.5-fold selectivity over the isomeric symmetric dimethyl arginine, depending on the surrounding sequence, with binding affinities in the low micromolar range. The affinity and selectivity of A2D for the different methylated states of Arg parallels that of proteins that bind to these PTMs. Characterization of the receptor–PTM complex indicates that cation−π interactions provide the main driving force for binding, loosely mimicking the binding mode found in the recognition of dimethyl arginine by native protein receptors.
Low Copy Numbers of DC-SIGN in Cell Membrane Microdomains: Implications for Structure and Function. Ping Liu, Xiang Wang, Michelle S. Itano, Aaron K. Neumann, Aravinda M. de Silva, Ken Jacobson, Nancy L. Thompson. Traffic, Volume 15, Issue 2, pages 179–196, February 2014.
The Cellular Environment Stabilizes Adenine Riboswitch RNA Structure. Jillian Tyrrell, Jennifer L. McGinnis, Kevin M. Weeks, and Gary J. Pielak . Biochemistry, Article ASAP, DOI: 10.1021/bi401207q.
Impact of Reconstituted Cytosol on Protein Stability. Mohona Sarkar, Austin E. Smith, and Gary J. Pielak. Published online before print, November 11, 2013, doi: 10.1073/pnas.1312678110 PNAS November 11, 2013.
Molecular Basis for pH-Dependent Mucosal Dehydration in Cystic Fibrosis Airways. Alaina L. Garlanda, William G. Waltonb, Raymond D. Coakley, Chong D. Tan, Rodney C. Gilmore, Carey A. Hobbs, Ashutosh Tripathy, Lucy A. Clunes, Sompop Bencharit, M. Jackson Stutts, Laurie Betts, Matthew R. Redinbo, and Robert Tarran. PNAS, September 16, 2013, doi: 10.1073/pnas.1311999110.
β-Turn Sequences Promote Stability of Peptide Substrates for Kinases Within the Cytosolic Environment. Shan Yang, Angela Proctor, Lauren L. Cline, Kaiulani M. Houston, Marcey L. Waters and Nancy L. Allbritton. Analyst, 2013,138, 4305-4311.
Lipid Pools As Photolabile "Protecting Groups": Design of Light-Activatable Bioagents. Luong T. Nguyen, Nathan P. Oien, Nancy L. Allbritton, David S. Lawrence. Angew. Chem., online 31 JUL 2013, DOI: 10.1002/anie.201305510.
A Serine-Substituted P450 Catalyzes Highly Efficient Carbene Transfer to Olefins In Vivo. Pedro Coelho, Jane Wang, Maraia Ener, Stefanie Baril, Arvind Kannan, Frances Arnold, and Eric Brustad. Nature Chemical Biology (2013) doi:10.1038/nchembio.1278.
Accurate SHAPE-Directed RNA Secondary Structure Modeling, Including Pseudoknots. Christine E. Hajdin, Stanislav Bellaousov, Wayne Huggins, Christopher W. Leonard, David H. Mathews, and Kevin M. Weeks. PNAS, 110 (14):5498-5503.
A Synthetic Receptor for Asymmetric Dimethyl Arginine. Lindsey I. James , Joshua E. Beaver , Natalie W. Rice , and Marcey L. Waters. J. Am. Chem. Soc., 2013, 135 (17), pp 6450–6455.
Long-Range Architecture in a Viral RNA Genome. Eva J. Archer, Mark A. Simpson, Nicholas J. Watts, Rory O'Kane, Bangchen Wang, Dorothy A. Erie, Alex McPherson, and Kevin M. Weeks. Biochemistry, 2013, 52 (18), pp 3182–3190.