Protein Engineering & Computational Protein Design

We specialize in the development of novel proteins with useful properties for their application in chemistry and biology. In particular, we are interested in developing designer biocatalysts for chemical synthesis as well as genetically-encoded biosensors based on fluorescent proteins for in vivo imaging applications. To achieve these goals, we develop and exploit multistate computational protein design methods to predict mutations leading to the desired protein property. More information on our research projects can be found in the Research section.

Latest Results

Broom A et al. (2020) Nature Communications 11, 4808

The creation of artificial enzymes is a key objective of computational protein design. Although de novo enzymes have been successfully designed, these exhibit low catalytic efficiencies, requiring directed evolution to improve activity. Here, we use room-temperature X-ray crystallography to study changes in the conformational ensemble during evolution of the designed Kemp eliminase HG3 (kcat/KM 146 M–1s–1). We observe that catalytic residues are increasingly rigidified, the active site becomes better pre-organized, and its entrance is widened. Based on these observations, we engineer HG4, an efficient biocatalyst (kcat/KM 103,000 M–1s–1) containing key first and second-shell mutations found during evolution. HG4 structures reveal that its active site is pre-organized and rigidified for efficient catalysis. Our results show how directed evolution circumvents challenges inherent to enzyme design by shifting conformational ensembles to favor catalytically-productive sub-states, and suggest improvements to the design methodology that incorporate ensemble modeling of crystallographic data.

Quote: "Computational enzyme design with a crystallographically derived backbone ensemble derived from a low-activity enzyme could obviate the need for directed evolution..."

Read more here.

 

Previous results can be found here.

 

Advanced Protein Engineering Training, Internships, Courses & Exhibition (APRENTICE) Program

Interested in pursuing graduate training in protein engineering? Find out more about the APRENTICE program by clicking on the image below.

 

Research Funding

We gratefully acknowledge support from the following agencies:

 

Keywords

Protein Engineering, Computational Protein Design, Multistate Design, Enzymes, Biocatalysis, Fluorescent Proteins, Protein Dynamics, Molecular Modeling, Protein Science, High-Performance Computing, Biological Chemistry

 

Contact info

Roberto Chica, Ph. D.
Associate Professor
Department of Chemistry and Biomolecular Sciences
University of Ottawa
10 Marie Curie
Ottawa, ON K1N 6N5
Canada

(613) 562-5800 x 1988
rchica at uottawa dot ca