Design of a Novel Globular Protein Fold with Atomic-Level Accuracy
Abstract
A major challenge of computational protein design is the creation of novel proteins with arbitrarily chosen three-dimensional structures. Here, we used a general computational strategy that iterates between sequence design and structure prediction to design a 93-residue α/β protein called Top7 with a novel sequence and topology. Top7 was found experimentally to be folded and extremely stable, and the x-ray crystal structure of Top7 is similar (root mean square deviation equals 1.2 angstroms) to the design model. The ability to design a new protein fold makes possible the exploration of the large regions of the protein universe not yet observed in nature.
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References and Notes
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We acknowledge the expert assistance of B. Shen in crystallographic phasing, modeling, and refinement of the TOP7 structure, C. Rohl for aiding in the incorporation of RosettaDesign into Rosetta, C. Strauss for helping to generate the initial models of Top7, T. Leeper for help with two-dimensional NMR studies, and R. Klevit and the Klevit laboratory for help with preliminary NMR characterization of Top7. Academic users can obtain licensing information for RosettaDesign at www.unc.edu/kuhlmanpg/rosettadesign.htm. The coordinates and structure factors for the Top7 x-ray crystal structure have been deposited in the PDB with accession code 1QYS. B.K. was supported by a fellowship from the Cancer Research Fund of the Damon Runyon–Walter Winchell Foundation. This work was also supported by NIH grants to G.V., B.L.S., and D.B.
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Published In
Science
Volume 302 | Issue 5649
21 November 2003
21 November 2003
Copyright
American Association for the Advancement of Science.
Submission history
Received: 21 July 2003
Accepted: 25 September 2003
Published in print: 21 November 2003
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Supporting Online Material
www.sciencemag.org/cgi/content/full/302/5649/1364/DC1
Materials and Methods
Tables S1 to S6
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