title: De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity.
abstract: In nature, structural specificity in DNA and proteins is encoded differently: In DNA, specificity arises from modular hydrogen bonds in the core of the double helix, whereas in proteins, specificity arises largely from buried hydrophobic packing complemented by irregular peripheral polar interactions. Here, we describe a general approach for designing a wide range of protein homo-oligomers with specificity determined by modular arrays of central hydrogen-bond networks. We use the approach to design dimers, trimers, and tetramers consisting of two concentric rings of helices, including previously not seen triangular, square, and supercoiled topologies. X-ray crystallography confirms that the structures overall, and the hydrogen-bond networks in particular, are nearly identical to the design models, and the networks confer interaction specificity in vivo. The ability to design extensive hydrogen-bond networks with atomic accuracy enables the programming of protein interaction specificity for a broad range of synthetic biology applications; more generally, our results demonstrate that, even with the tremendous diversity observed in nature, there are fundamentally new modes of interaction to be discovered in proteins.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Boyken
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Graduate Program in Biological Physics, Structure, and Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Electrical Engineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Groves
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Langan
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Gustav
authors.initials: G
authors.lastname: Oberdorfer
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Ford
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Gilmore
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: DiMaio
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/3, 8010-Graz, Austria. Joint BioEnergy Institute, Emeryville, CA 94608, USA.
authors.forename: Jose Henrique
authors.initials: JH
authors.lastname: Pereira
authors.affiliation: Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Banumathi
authors.initials: B
authors.lastname: Sankaran
authors.affiliation: Department of Electrical Engineering, University of Washington, Seattle, WA 98195, USA. Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Seelig
authors.affiliation: Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. The Center for Advanced Mathematics for Energy Research Applications, Lawrence Berkeley National Laboratories, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Zwart
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. dabaker@u.washington.edu.
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D015202:Protein Engineering / Q000379:methods*; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*
chemical_list: D011506:Proteins