Protein folding and protein interactions underlie both proper function and disease in the nervous system. Many receptor proteins signal through complex interactions and rearrangements, and some proteins, such as the Parkinson’s Disease protein α-synuclein, misfold into toxic conformations. Studying these protein motions not only aids our understanding of diverse biological phenomena, it also contributes to an important fundamental problem in biochemistry: understanding how proteins fold and change shape.  The Petersson laboratory is developing tools to address questions of how peptides and proteins mediate cellular communication and how the cellular environment catalyzes protein misfolding, from detailed in vitro folding studies to tracking protein aggregation in neurons. These tools include novel chromophores, which we synthesize and incorporate into proteins through unnatural amino acid mutagenesis and synthetic protein ligation. In many cases, protein misfolding is regulated by post-translational modifications, for which we study the enzymes that install them, both to understand their biological roles and to utilize them in synthetic protein modification.  Finally, an area of particular interest in the Petersson laboratory is the introduction of thioamide modifications to the peptide backbone, which can serve as protein folding probes, or stabilizers for improved therapeutic peptides or in vivo imaging reagents.




Minimal Chromophores to Monitor Protein Motions

Fluorescence and FRET measurements can be used to glean time-resolved structural information on protein motions.  However, the relatively large size of common fluorophores can lead them to disrupt the very process they are meant to report on.  We have developed fluorescent amino acids and reagents that can be used to label a protein without disrupting its fold or function.




Computational Modeling of Dynamic Protein Structures

In order to acheive structural models of disordered proteins and protein conformational motions, we use distance data from FRET and other measurements to drive Monte Carlo simulations. We are currently designing scripts to predict favorable FRET labeling strategies and model amyloid protein aggregates as well. Once optimized, our scripts in Rosetta will be made publicly available so that others may use them for their own proteins of interest.




Toward a Molecular Understanding of Parkinson's Disease

Parkinson's Disease is one of the leading causes of death in the United States, yet its etiology remains unknown. Using the tools of chemical protein modification, we study the molecular basis for the disease, both through in vitro stduies of the misfolding of purified proteins like alpha-synuclein and tau, as well as through microscopy studies that allow us to observe the affects of aggregated proteins in cells (performed in collaboration with Center for Neurodegeneraive Disease Reseach).




Thioamide Modifications of the Protein Backbone

Thioamides have subtly different steric and electronic properties than oxoamides that allow them to precisely disrupt protein interactions, or act as site-specific photoswitches or fluorescence quenchers. We have shown that thioamides can be used to monitor protein folding and proteolysis using fluorescence, and that thioamide-modified peptides can be stable and bioactive.





Post-Translational Modification Enzymology and Applications

N-terminal protein modifications are ubiquitous (85% of mammalian proteins are acetylated) and govern many Important cellular processes such as protein-protein interactions and degradation. We study the molecular basis for these modifications and utilize these and other enzymes as tools for manipulating proteins and attaching functional groups to their termini.


    We are currently funded by the following agencies:

The National Science Foundation (CHE-1708759)



The National Institutes of Health (NS081033, NS103873, and GM127593)