Patricia Clark

O'Hara Professor of Chemistry & Biochemistry; Associate Vice President for Research; Director, Biophysics Instrumentation Core Facility

317E Main Building
Notre Dame, IN 46556
+1 574-631-8353

Research Areas

  • Biochemistry
  • Physical/Analytical Chemistry

Research Specialties

  • Life Processes
  • Measurement
  • Medicine

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Year Title
2021-present Associate Vice President for Research, University of Notre Dame
2018-present Founder & Director, Biophysics Instrumentation Core Facility, University of Notre Dame
2017-2021 Founder & Director, Biophysics Graduate Program, University of Notre Dame
2013-2014 Provost Fellow, University of Notre Dame
2013-present Professor of Chemistry & Biochemistry, University of Notre Dame
2011-2012 Associate Department Chair, Department of Chemistry & Biochemistry, University of Notre Dame
2011-present Concurrent Professor of Chemical & Biomolecular Engineering, University of Notre Dame
2010-present Rev. John Cardinal O'Hara, CSC, Professor of Biochemistry, University of Notre Dame
2008-2013 Associate Professor, University of Notre Dame
2001-2006 Clare Boothe Luce Assistant Professor of Biochemistry, University of Notre Dame
1997-2001 Postdoctoral Fellow, Massachusetts Institute of Technology
1997 Ph.D. in Molecular Biophysics, University of Texas Southwestern Medical Center at Dallas
1991 B.S. in Chemistry, Georgia Institute of Technology

Selected Awards

2023   Dorothy Crowfoot Hodgkin Award, The Protein Society

2022   Fellow, American Association for the Advancement of Science

2021   NIH Director's Pioneer Award (DP1)

2018   Research Grant, W.M. Keck Foundation

2018   63rd Annual Francis Clifford Phillips Lecturer, University of Pittsburgh

2018,2013   Rev. Edmund Joyce Award for Excellence in Undergraduate Education

2017   Peter B. Sherry Memorial Lecturer, Georgia Institute of Technology

2017   Elected Chair, Biopolymers In Vivo Subgroup, Biophysical Society

2015   President, Gibbs Society for Biothermodynamics

2013   Michael and Kate Barany Award for Young Investigators, Biophysical Society

2003   American Heart Association National Scientist Development Award

2003   NSF CAREER Award

1998   NIH NRSA Postdoctoral Fellowship

1994   NIH Biophysics Predoctoral Training Fellowship

Curriculum Vitae

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.

Selected Publications

  • Baxa, M. C.; Lin, X. X.; Mukinay, C. D.; Chakravarthy, S.; Sachleben, J. R.; Antilla, S.; Hartrampf, N.; Riback, J. A.; Gagnon, I. A.; Pentelute, B. L.; Clark, P. L. and Sosnick, T. R. "How Hydrophobicity, Side Chains, and Salt Affect the Dimensions of Disordered Proteins" 2024 Protein Science, 33 (5), e4986. DOI: 10.1002/pro.4986.
  • Lundgren, T. J.; Clark, P. L. and Champion, M. M. "Fit for Purpose Approach to Evaluate Detection of Amino Acid Substitutions in Shotgun Proteomics" 2024 Journal of Proteome Research, 23 (4), pp.1263-1271. DOI: 10.1021/acs.jproteome.3c00730.
  • Newaz, K.; Piland, J.; Clark, P. L.; Emrich, S. J.; Li, J. and Milenkovic, T. "Multi-Layer Sequential Network Analysis Improves Protein 3D Structural Classification" 2022 Proteins-Structure Function and Bioinformatics, in press. DOI: 10.1002/prot.26349.
  • Wright, G.; Rodriguez, A.; Li, J.; Milenkovic, T.; Emrich, S. J. and Clark, P. L. "CHARMING: Harmonizing Synonymous Codon Usage to Replicate a Desired Codon Usage Pattern" 2022 Protein Science, 31 (1), pp.221-231. DOI: 10.1002/pro.4223.
  • Harkness, R. W.; Toyama, Y.; Ripstein, Z. A.; Zhao, H. Y.; Sever, A.; Luan, Q.; Brady, J. P.; Clark, P. L.; Schuck, P. and Kay, L. E. "Competing Stress-Dependent Oligomerization Pathways Regulate Self-Assembly of the Periplasmic Protease-Chaperone DegP" 2021 Proceedings of the National Academy of Sciences of the United States of America, 118 (32), e2109732118. DOI: 10.1073/pnas.2109732118.
  • Bowman, M. A.; Riback, J. A.; Rodriguez, A.; Guo, H. Y.; Li, J.; Sosnick, T. R. and Clark, P. L. "Properties of Protein Unfolded States Suggest 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.

Visit Patricia Clark's publications at PubMed