Computational design of a homotrimeric metalloprotein with a trisbipyridyl core

Journal Article · Thu Dec 08 00:00:00 EST 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1600188113· OSTI ID:1335049

Mills, Jeremy H. ^[1]; Sheffler, William ^[2]; Ener, Maraia E. ^[3]; Almhjell, Patrick J. ^[4]; Oberdorfer, Gustav ^[2]; Pereira, José Henrique ^[5]; Parmeggiani, Fabio ^[2]; Sankaran, Banumathi ^[6]; Zwart, Peter H. ^[6]; Baker, David ^[7]

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1. Department of Biochemistry and the Institute for Protein Design, University of Washington, Seattle, WA 98195,, School of Molecular Sciences, Arizona State University, Tempe, AZ 85281,, The Biodesign Center for Molecular Design and Biomimetics, Arizona State University, Tempe, AZ 85281,
2. Department of Biochemistry and the Institute for Protein Design, University of Washington, Seattle, WA 98195,
3. Department of Biochemistry and the Institute for Protein Design, University of Washington, Seattle, WA 98195,, Department of Chemistry, University of Washington, Seattle, WA 98195,
4. School of Molecular Sciences, Arizona State University, Tempe, AZ 85281,, The Biodesign Center for Molecular Design and Biomimetics, Arizona State University, Tempe, AZ 85281,
5. Joint BioEnergy Institute, Emeryville, CA 94608,
6. Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720,
7. Department of Biochemistry and the Institute for Protein Design, University of Washington, Seattle, WA 98195,, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

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 in this paper, 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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES); US Department of the Navy, Office of Naval Research (ONR); National Institutes of Health (NIH)
• Grant/Contract Number: AC02-05CH11231; N00014-14-1-0757
• OSTI ID: 1335049
• Alternate ID(s): OSTI ID: 1379621
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 113 Journal Issue: 52; ISSN 0027-8424
• Publisher: Proceedings of the National Academy of Sciences
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES
computational protein design
noncanonical amino acids
metalloproteins
protein self-assembly