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.
Genetically encoded, light-activatable proteins provide the means to probe biochemical pathways at specific subcellular locations with exquisite temporal control. However, engineering these systems in order to provide a dramatic jump in localized activity, while retaining a low dark-state background remains a significant challenge.
When placed within the framework of a genetically encodable, light-activatable heterodimerizer system, the actin-remodelling protein cofilin induces dramatic changes in the F-actin network and consequent cell motility upon illumination. In an article published in Angewandte Chemie, International Edition, researchers in the David Lawrence Group, demonstrate that the use of a partially impaired mutant of cofilin is critical for maintaining low background activity in the dark. They also show that light-directed recruitment of the reduced activity cofilin mutants to the cytoskeleton is sufficient to induce F-actin remodeling, formation of filopodia, and directed cell motility.
Many central biological processes are mediated by complex RNA structures, but the higher-order interactions for most RNAs are unknown, which makes it difficult to understand how RNA structure governs function. As published in Nature Methods, a team of students in the Weeks lab have invented a new approach -- selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) -- that makes possible de novo and large-scale identification of RNA functional motifs.
SHAPE-MaP melds chemistry invented in the Weeks lab with readout by massively parallel sequencing to make it possible to detect structure-selective chemical reactions in RNA on genome-wide scales. SHAPE-MaP represents a "no compromises" approach for interrogating the structure of RNA, enables analysis of low-abundance RNAs, and is ultimately poised to democratize RNA-structure analysis.
Local Iontophoretic Administration of Cytotoxic Therapies to Solid Tumors. James D. Byrne, Mohammad N. R. Jajja, Adrian T. O’Neill, Lissett R. Bickford, Amanda W. Keeler, Nabeel Hyder, Kyle Wagner, Allison Deal, Ryan E. Little, Richard A. Moffitt, Colleen Stack, Meredith Nelson, Christopher R. Brooks, William Lee, J. Chris Luft, Mary E. Napier, David Darr, Carey K. Anders, Richard Stack, Joel E. Tepper, Andrew Z. Wang, William C. Zamboni, Jen Jen Yeh, and Joseph M. DeSimone. Sci Transl Med 4 February 2015: Vol. 7, Issue 273, p. 273ra14.
Quinary Structure Modulates Protein Stability in Cells. William B. Monteith, Rachel D. Cohen, Austin E. Smith, Emilio Guzman-Cisneros, and Gary J. Pielak. PNAS, Early Edition, doi 10.1073 pnas.1417415112 .
Cell-Mediated Assembly of Phototherapeutics. Weston J. Smith, Nathan P. Oien, Robert M. Hughes, Christina M. Marvin, Zachary L. Rodgers, Junghyun Lee and David S. Lawrence. Angewandte Chemie International Edition, Volume 53, Issue 41, pages 10945-10948, October 6, 2014.
Optogenetic Engineering: Light-Directed Cell Motility. Robert M. Hughes and David S. Lawrence. Angewandte Chemie International Edition, Volume 53, Issue 41, pages 10904-10907, October 6, 2014.
RNA Motif Discovery by SHAPE and Mutational Profiling (SHAPE-MaP). Nathan A Siegfried, Steven Busan, Greggory M Rice, Julie A E Nelson & Kevin M Weeks. Nature Methods 11, 959–965 (2014).
Residue Level Quantification of Protein Stability in Living Cells. William B. Monteith and Gary J. Pielak. PNAS July 21, 2014, doi: 10.1073/pnas.1406845111 .
Nitric Oxide-Releasing Quaternary Ammonium-Modified Poly(amidoamine) Dendrimers as Dual Action Antibacterial Agents. Brittany V. Worley , Danielle L. Slomberg , and Mark H. Schoenfisch. Bioconjugate Chem., 2014, 25 (5), pp 918–927.
Protein Crowder Charge and Protein Stability. Mohona Sarkar, Joe Lu, and Gary Pielak. Biochemistry, 2014, 53 (10), pp 1601–1606.
Strategies for Protein NMR in Escherichia coli. Guohua Xu, Yansheng Ye, Xiaoli Liu, Shufen Cao, Qiong Wu, Kai Cheng, Maili Liu, Gary J. Pielak, and Conggang Li. Biochemistry, 2014, 53 (12), pp 1971–1981.
Long-Wavelength Fluorescent Reporters for Monitoring Protein Kinase Activity. Nathan P. Oien, Luong T. Nguyen, Dr. Finith E. Jernigan, Prof. Melanie A. Priestman and Prof. David S. Lawrence. Article first published online: 6 MAR 2014, DOI: 10.1002/anie.201309691.