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Computational protein design has taken big strides in recent years; however, the tools available are still not at a state where a sequence can be designed to fold into a given protein structure at will and with high probability. We have applied here a recent release of Rosetta Design to redesign a set of structurally very similar proteins belonging to the thioredoxin fold. We used a genetic screening tool to estimate solubility/folding of the designed proteins in E. coli and to select the best hits from this for further biochemical characterization. We have previously used this set of template proteins for redesign and found that success was highly dependent on template structure, a trait which was also found in this study. Nevertheless, state-of-the-art design software is now able to predict the best template, most likely due to the introduction of an energy term that reports on stress in covalent bond lengths and angles. The template that led to the greatest fraction of successful designs was the same (a thioredoxin from spinach) as that identified in our previous study. Our previously described redesign of thioredoxin, which also used the spinach protein as a template, however also performed well as a template. In the present study, both of these templates yielded proteins with compact folded structures and enforced the conclusion that any design project must carefully consider different design templates. Fortunately, selecting designs based on energies appears to correctly identify such templates.


Frederikke Isa Marin, Kristoffer Enøe Johansson, Charlotte O'Shea, Kresten Lindorff-Larsen, Jakob Rahr Winther. Computational and Experimental Assessment of Backbone Templates for Computational Redesign of the Thioredoxin Fold. The journal of physical chemistry. B. 2021 Oct 14;125(40):11141-11149

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PMID: 34592819

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