Computational design of a homotrimeric metalloprotein with a trisbipyridyl core

Jeremy H Mills, William Sheffler, Maraia E Ener, Patrick J Almhjell, Gustav Oberdorfer, José Henrique Pereira, Fabio Parmeggiani, Banumathi Sankaran, Peter H Zwart, David Baker

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Metal-chelating heteroaryl small molecules have found widespread use as building blocks for coordination-driven, self-assembling nanostructures. The metal-chelating noncanonical amino acid (2,2'-bipyridin-5yl)alanine (Bpy-ala) could, in principle, be used to nucleate specific metalloprotein assemblies if introduced into proteins such that one assembly had much lower free energy than all alternatives. Here we describe the use of the Rosetta computational methodology to design a self-assembling homotrimeric protein with [Fe(Bpy-ala)3]2+ complexes at the interface between monomers. X-ray crystallographic analysis of the homotrimer showed that the design process had near-atomic-level accuracy: The all-atom rmsd between the design model and crystal structure for the residues at the protein interface is ∼1.4 Å. These results demonstrate that computational protein design together with genetically encoded noncanonical amino acids can be used to drive formation of precisely specified metal-mediated protein assemblies that could find use in a wide range of photophysical applications.

Original languageEnglish
Pages (from-to)15012-15017
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
Early online date8 Dec 2016
Publication statusPublished - 27 Dec 2016


  • Amino Acids
  • Cloning, Molecular
  • Computational Biology
  • Computer Simulation
  • Crystallography, X-Ray
  • Metalloproteins
  • Metals
  • Models, Molecular
  • Protein Conformation
  • Protein Engineering
  • Protein Interaction Mapping
  • Protein Multimerization
  • Pyridines
  • Software
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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