DEPARTMENT OF CHEMISTRY

Affiliations

Department of Chemistry

Department of Cell & Developmental Biology

International Institute of Nanotechnology

Center for Synthetic Biology

Robert H. Lurie Comprehensive Cancer Center

Research Statement

My group uses the tools of organic chemistry, materials science, engineering and biochemistry to address important challenges at the intersection of chemistry and biology. Our group pioneered a new platform for engineering protein-based molecules – called Megamolecules – where fusion proteins react with synthetic linkers to create multi-component, complex architectures. The modular megamolecule approach can position protein domains in configurations that are not accessible with traditional protein engineering techniques, including branched, cyclic, and dendritic structures, and can produce structures with dimensions that exceed 100 nm and molecular weights greater than 1 M Dalton. Synthesis of these complex structures is made possible by a new and highly efficient strategy for linking molecules together: the use of covalent inhibitors that react selectively and rapidly with their target enzyme domains. This approach greatly increases the rates and yields for conjugation compared to common bioconjugation techniques.  Currently, we are developing megamolecules for a diverse range of applications, including dynamic protein structures and antibody mimics that act as diagnostics and therapeutics. Our group also developed Self-Assembled Monolayers for MALDI Mass Spectrometry (SAMDI-MS) –  an approach for using mass spectrometry and arrays of self-assembled monolayers to perform quantitative experiments in high throughput. The SAMDI technique can measure chemical reactions and enzymatic post-translational modifications – including kinase, protease, methyltransferase and carbohydrate-directed modifications. We have used this platform for a wide range of studies, including the use of carbohydrate arrays to discover novel enzymes, the preparation of peptide arrays to profile the enzyme activities in cell lysates and high throughput screening to discover novel reactions and small molecular modulators.

Selected Publications

Development of an Enzyme-Inhibitor Reaction Using Cellular Retinoic Acid Binding Protein II for One-Pot Megamolecule Assembly. B. R. Kimmel and M. Mrksich  Chem. Eur. J. 2021, 27, 17843–17848.

Synthesis, Characterization and Simulation of Four-Armed Megamolecules.  S. Zhou, P. He, S. Dhindwal, V. Grum-Tokars, Y. Li; K. Parker, J. Modica, R. Bleher, R. dos Reis, J. Zuchniarz, V. Dravid, G. Voth; B. Roux, M. Mrksich  Biomacromolecules, 2021, 22, 2363–2372.

Synthetic Tuning of Domain Stoichiometry in Nanobody-Enzyme Mega-molecules. K. J. Metcalf, B. R. Kimmel, D. J. Sykora, J. A. Modica, K. A. Parker, E. Berens, R. Dai, V. P. Dravid, Z. Werb and M. Mrksich  Bioconjugate Chem., 2021, 32, 143-152. 

Design and Synthesis of Megamolecule Mimics of a Therapeutic Antibody. J. Modica, T. Iderzorig, and M. Mrksich  J. Am. Chem. Soc., 2020, 142, 13657-13661. 

Solid-Phase Synthesis of Megamolecules.  B. R. Kimmel, J. A. Modica, K. Parker, V. Dravid and M. Mrksich  J. Am. Chem. Soc., 2020, 142, 4534-4538. 

High Throughput Screening with SAMDI Mass Spectrometry for Directed Evolution. A. J. Pluchinsky, D. W. Wackelin, X. Huang, F. H. Arnold, M. Mrksich  J. Am. Chem. Soc., 2020, 142, 19804-19808.

A High-Throughput Photocapture Approach for Reaction Discovery.  A. A. Bayly, B. R. McDonald, K. A.  Scheidt and M. Mrksich  PNAS, 2020, 117, 13261-13266.

Synthesis of Cyclic Megamolecules.  J.A Modica, Y. Lin and M. Mrksich   J. Am. Chem. Soc., 2018, 140, 6391-6399. 

Long-Range Energy Transfer in Protein Megamolecules.  E.L. Taylor, K.J. Metcalf, B. Carlotti, C.-T. Lai, J.A. Modica, G.C. Schatz, M. Mrksich and T. Goodson  J. Am. Chem. Soc.,  2018, 140, 15731-15743. 

High-Throughput Mapping of CoA Metabolites by SAMDI-MS to Optimize the Cell-Free Biosynthesis of HMG-CoA.  P. O’Kane, Q. Dudley, A. McMillan, M. Jewett and M. Mrksich  Science Advances, 2019, 5, eaaw9180. 

Selected Honors/Awards:

• 2020 Pittsburgh Analytical Chemistry Award
• 2016 iBIO iCON Innovator Award
• 2016 Phi Lambda Epsilon Award Lecture,  University of Nebraska
• 2016 Henry Werner Lecturer,  University of Kansas
• 2012 Fellow, American Institute for Medical and Biological Engineering  
• 2008 Margaret Etter Lecture, University of Minnesota
• 2007 Murtiashaw Lecture, University of South Carolina
• 2005 Fellow, American Association for the Advancement of Science
• 2003 ACS Arthur C. Cope Young Scholar Award
• 2002 R.C. Fuson Visiting Scholar, University of Illinois
• 2002 TR100 Young Innovator Award
• 2000 Sara Jane Rhoads and Rebecca Raulins Lecturer, University of Wyoming
• 2000 Camille Dreyfus Teacher-Scholar Award
• 2000 Sloan Research Fellow
• 1996-2001 Camille and Henry Dreyfus New Faculty Award
• 1996-1999 Searle Scholar Award
• 1994-1996 American Cancer Society Postdoctoral Fellow
• 1993-1994 Ralph M. Parsons Foundation Graduate Fellow
• 1990-1993 National Institutes of Health National Research Service Award
• 1989 University of Illinois Marvel Undergraduate Research Award