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The unexpected structure of the designed protein Octarellin V.1 forms a challenge for protein structure prediction tools

DOI: 10.1016/j.jsb.2016.05.004 DOI Help

Authors: Maximiliano Figueroa (University of Liège) , Mike Sleutel (Vrije Universiteit Brussel) , Marylene Vandevenne (University of Liège) , Gregory Parvizi (University of Liège) , Sophie Attout (University of Liège) , Olivier Jacquin (University of Liège) , Julie Vandenameele (University of Liège) , Axel W. Fischer (Vanderbilt University) , Christian Damblon (Univeristy of Liège) , Erik Goormaghtigh (Université Libre de Bruxelles) , Marie Valerio-lepiniec (Université Paris-Sud) , Agathe Urvoas (Université Paris-Sud) , Dominique Durand (Université Paris-Sud) , Els Pardon (Vrije Universiteit Brussel; Structural Biology Research Center, VIB) , Jan Steyaert (Vrije Universiteit Brussel; Structural Biology Research Center, VIB) , Philippe Minard (Université Paris-Sud) , Dominique Maes (Vrije Universiteit Brussel) , Jens Meiler (Vanderbilt University) , André Matagne (University of Liège) , Joseph A. Martial (University of Liège) , Cécile Van De Weerdt (University of Liège)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Structural Biology , VOL 195 , PAGES 19 - 30

State: Published (Approved)
Published: July 2016

Abstract: Despite impressive successes in protein design, designing a well-folded protein of more 100 amino acids de novo remains a formidable challenge. Exploiting the promising biophysical features of the artificial protein Octarellin V, we improved this protein by directed evolution, thus creating a more stable and soluble protein: Octarellin V.1. Next, we obtained crystals of Octarellin V.1 in complex with crystallization chaperons and determined the tertiary structure. The experimental structure of Octarellin V.1 differs from its in silico design: the (αβα) sandwich architecture bears some resemblance to a Rossman-like fold instead of the intended TIM-barrel fold. This surprising result gave us a unique and attractive opportunity to test the state of the art in protein structure prediction, using this artificial protein free of any natural selection. We tested 13 automated webservers for protein structure prediction and found none of them to predict the actual structure. More than 50% of them predicted a TIM-barrel fold, i.e. the structure we set out to design more than 10 years ago. In addition, local software runs that are human operated can sample a structure similar to the experimental one but fail in selecting it, suggesting that the scoring and ranking functions should be improved. We propose that artificial proteins could be used as tools to test the accuracy of protein structure prediction algorithms, because their lack of evolutionary pressure and unique sequences features.

Journal Keywords: De novo design; Artificial proteins; Protein design; Molecular modeling

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography