Patricia L. Clark

Patricia L. Clark

Protein Biophysics in Living Cells


Rev. John Cardinal O'Hara C.S.C. Professor of Biochemistry, University of Notre Dame
Concurrent Professor, Chemical & Biomolecular Engineering, University of Notre Dame
Rev. John Cardinal O'Hara C.S.C. Associate Professor of Biochemistry,University of Notre Dame
Associate Professor, University of Notre Dame
Assistant 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
B.S. in Chemistry, Georgia Institute of Technology

Selected Awards

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
NIH NRSA Postdoctoral Fellowship
NIH Biophysics Predoctoral Training Fellowship

Research Interests

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.

Recent Papers

  • Walsh, I.M., Bowman, M.A., Clark, P.L. " Synonymous codon substitutions impair cell fitness" 2019 bioRxiv. DOI: 10.1101/666552
  • Riback, J.A., Bowman, M.A., Zmyslowski, A.M., Plaxco, K.W., Sosnick, T.R., Clark, P.L. "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
  • Rodriguez, A., Wright, G., Emrich, S., Clark, P.L. "%MinMax: A versatile tool for calculating and comparing synonymous codon usage and its impact on protein folding" 2018 Protein Science, 27 (1), pp. 356-362. DOI: 10.1002/pro.3336
  • Faisal, F.E., Newaz, K., Chaney, J.L., Li, J., Emrich, S.J., Clark, P.L., Milenković, T. "GRAFENE: Graphlet-based alignment-free network approach integrates 3D structural and sequence (residue order) data to improve protein structural comparison" 2017 Scientific Reports, 7 (1), 14890. DOI: 10.1038/s41598-017-14411-y
  • Riback, J.A., Bowman, M.A., Zmyslowski, A.M., Knoverek, C.R., Jumper, J.M., Hinshaw, J.R., Kaye, E.B., Freed, K.F., Clark, P.L., Sosnick, T.R. "Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water" 2017 Science, 358 (6360), pp. 238-241. DOI: 10.1126/science.aan5774
  • Chaney, J.L., Steele, A., Carmichael, R., Rodriguez, A., Specht, A.T., Ngo, K., Li, J., Emrich, S., Clark, P.L. "Widespread position-specific conservation of synonymous rare codons within coding sequences" 2017 PLoS Computational Biology, 13 (5), e1005531. DOI: 10.1371/journal.pcbi.1005531

Visit Patricia Clark's publications at PubMed


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