Computational design of self-assembling cyclic protein homo-oligomers.
Self-assembling cyclic protein homo-oligomers play important roles in biology, and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue-pair-transform method to assess the designability of a protein-protein interface. This method is sufficiently rapid to enable the systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were characterized experimentally, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (four homodimers, six homotrimers, six homotetramers and one homopentamer) had solution small-angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each is very close to their corresponding computational model.
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
Jorge A
JA
Fallas
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
George
G
Ueda
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
William
W
Sheffler
Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
Vanessa
V
Nguyen
Department of Chemistry and Biochemistry, University of California Los Angles, Los Angeles, California 90095, USA.
Dan E
DE
McNamara
Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, Berkeley, California 94720, USA.
Banumathi
B
Sankaran
Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, Berkeley, California 94720, USA.|Joint BioEnergy Institute, Emeryville, California 94608, USA.
Jose Henrique
JH
Pereira
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
Fabio
0000-0001-8548-1090
F
Parmeggiani
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
T J
TJ
Brunette
Department of Chemistry and Biochemistry, University of California Los Angles, Los Angeles, California 90095, USA.
Duilio
D
Cascio
Department of Chemistry and Biochemistry, University of California Los Angles, Los Angeles, California 90095, USA.
Todd R
TR
Yeates
Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory, Berkeley, California 94720, USA.
Peter
P
Zwart
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
David
D
Baker
D005583:Fourier Analysis; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
D011506:Proteins