- Associate Vice President for Research Development, University of Notre Dame
- Founder & Director, Biophysics Instrumentation Core Facility, University of Notre Dame
- Founder & Director, Biophysics Graduate Program, University of Notre Dame
- Provost Fellow, University of Notre Dame
- Professor of Chemistry & Biochemistry, University of Notre Dame
- Associate Department Chair, Department of Chemistry & Biochemistry, University of Notre Dame
- Concurrent Professor of Chemical & Biomolecular Engineering, University of Notre Dame
- Rev. John Cardinal O'Hara, CSC, Professor of Biochemistry, University of Notre Dame
- Associate Professor, University of Notre Dame
- Clare Boothe Luce Assistant Professor of Biochemistry, University of Notre Dame
- Postdoctoral Fellow, Massachusetts Institute of Technology
- Ph.D. in Molecular Biophysics, University of Texas Southwestern Medical Center at Dallas
- B.S. in Chemistry, Georgia Institute of Technology
- Research Grant, W.M. Keck Foundation
- 63rd Annual Francis Clifford Phillips Lecturer, University of Pittsburgh
- Rev. Edmund Joyce Award for Excellence in Undergraduate Education
- Peter B. Sherry Memorial Lecturer, Georgia Institute of Technology
- Elected Chair, Biopolymers In Vivo Subgroup, Biophysical Society
- President, Gibbs Society for Biothermodynamics
- Michael and Kate Barany Award for Young Investigators, Biophysical Society
- American Heart Association National Scientist Development Award
- NSF CAREER Award
- NIH NRSA Postdoctoral Fellowship
- NIH Biophysics Predoctoral Training Fellowship
Proteins are long flexible polymers of amino acids, yet each must fold into a complex 3D shape in order to carry out a specific catalytic, binding, or structural activity. Experiments with purified proteins have demonstrated that the information needed for a given protein to obtain its final folded structure is contained within the sequence of its amino acid residues. However, the rules that dictate how a given sequence will fold into a given structure are still unclear. Understanding the rules of protein folding is of utmost importance for predicting protein structure from genomic sequence data, designing novel proteins, and understanding how and why protein folding mechanisms can fail. Failure of protein folding mechanisms, often due to genetic mutations or adverse conditions such as thermal or chemical stress, is the cause of numerous human diseases including cystic fibrosis, Alzheimer's disease, juvenile cataracts, and many forms of cancer.
Research in the Clark laboratory is focused on two related topics. First, how are the rules for protein folding affected by their native environment, the cell? In the cell, proteins are synthesized in a vectorial fashion. The energy landscape for folding during chain synthesis (or secretion across a membrane) is hence quite different from the energy landscape for the folding of a full-length polypeptide chain. As a result, folding intermediates populated during refolding in vitro might be populated quite differently during vectorial folding. A particular interest in the Clark laboratory is the role of co-translational protein folding in suppressing chain misfolding and aggregation in vivo. A related interest is the display of virulence factors on the outer surface of pathogenic gram-negative bacteria. For example, these virulence proteins must fold only after secretion across two membranes; what prevents them from folding prematurely in the periplasm?
Second, what are the protein folding rules that govern the formation of β-sheet structure? β-sheets represent a type of regular, repeating protein structure, characterized by an extensive hydrogen bonding network between strands of amino acid residues. Contacts between individual amino acid residues in β-sheets often represent contacts quite distant in sequence. As a result, it has been extremely difficult to define simple rules for β-sheet formation, and we expect that high contact order will make many β-sheet topologies difficult (if not impossible) to form co-translationally. We are using an extremely simple β-sheet architecture, the parallel β-helix, as a model system for developing rules for β-sheet formation.
- Bowman, M.A., Riback, J.A., Rodriguez, A., Gao, H., Li, J., Sosnick, T.R., Clark, P.L. "Properties of Protein Unfolded States Suggests Broad Selection for Expanded Conformational Ensembles" 2020 Proceedings of the National Academy of Sciences of the United States of America, 117 (38), pp. 23356-23364. DOI:10.1073/pnas.2003773117.
- Newaz, K., Wright, G., Piland, J., Li, J., Clark, P.L., Emrich, S.J., Milenkovic, T. "Network Analysis of Synonymous Codon Usage" 2020 Bioinformatics, btaa603. DOI:10.1093/bioinformatics/btaa603.
- Clark, P. L., Plaxco, K. W., Sosnick, T. R. "Water as a Good Solvent for Unfolded Proteins: Folding and Collapse are Fundamentally Different" 2020 Journal of Molecular Biology, 432 (9), pp. 2882-2889. DOI:10.1016/j.jmb.2020.01.031.
- Walsh, I. M., Bowman, M. A., Soto Santarriaga, I. F., Rodriguez, A., Clark, P. L. "Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness" 2020 Proceedings of the National Academy of Sciences of the United States of America, 117 (7), pp. 3528-3534. DOI:10.1073/pnas.1907126117.
- Wright, G., Rodriguez, A., Li, J., Clark, P. L., Milenković, T., Emrich, S. J. "Analysis of computational codon usage models and their association with translationally slow codons" 2020 PLoS ONE, 15 (4), DOI:10.1371/journal.pone.0232003.
- Riback, J. A., Bowman, M. A., Zmyslowski, A. M., Plaxco, K. W., Clark, P. L., Sosnick, T. R. "Commonly used FRET fluorophores promote collapse of an otherwise disordered protein" 2019 Proceedings of the National Academy of Sciences of the United States of America, 116 (18), pp. 8889-8894. DOI:10.1073/pnas.1813038116.