De novo design of a fluorescence-activating β-barrel

Jiayi Dou, Anastassia A. Vorobieva, William Sheffler, Lindsey A. Doyle, Hahnbeom Park, Matthew J. Bick, Binchen Mao, Glenna W. Foight, Min Yen Lee, Lauren A. Gagnon, Lauren Carter, Banumathi Sankaran, Sergey Ovchinnikov, Enrique Marcos, Po-Ssu Huang, Joshua C. Vaughan, Barry L. Stoddard and David Baker ()
Additional contact information
Jiayi Dou: University of Washington
Anastassia A. Vorobieva: University of Washington
William Sheffler: University of Washington
Lindsey A. Doyle: Fred Hutchinson Cancer Research Center
Hahnbeom Park: University of Washington
Matthew J. Bick: University of Washington
Binchen Mao: University of Washington
Glenna W. Foight: University of Washington
Min Yen Lee: University of Washington
Lauren A. Gagnon: University of Washington
Lauren Carter: University of Washington
Banumathi Sankaran: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory
Sergey Ovchinnikov: University of Washington
Enrique Marcos: University of Washington
Po-Ssu Huang: University of Washington
Joshua C. Vaughan: University of Washington
Barry L. Stoddard: Fred Hutchinson Cancer Research Center
David Baker: University of Washington

Nature, 2018, vol. 561, issue 7724, 485-491

Abstract: Abstract The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli, yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures.

Keywords: Backbone Hydrogen Bonds; Ligand Docking Simulations; Scaffold Position; Hydrophobic Packing Interactions; Rotamers (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0509-0

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