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Title: Computational design of a homotrimeric metalloprotein with a trisbipyridyl core

Abstract

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.

Authors:
 [1];  [2];  [3];  [4];  [2];  [5];  [2];  [6];  [6];  [7]
  1. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry and the Inst. for Protein Design; Arizona State Univ., Tempe, AZ (United States). School of Molecular Sciences; Arizona State Univ., Tempe, AZ (United States). Biodesign Center for Molecular Design and Biomimetics
  2. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry and the Inst. for Protein Design
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry and the Inst. for Protein Design; Univ. of Washington, Seattle, WA (United States). Dept. of Chemistry
  4. Arizona State Univ., Tempe, AZ (United States). School of Molecular Sciences; Arizona State Univ., Tempe, AZ (United States). Biodesign Center for Molecular Design and Biomimetics
  5. Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States)
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging Division
  7. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry and the Inst. for Protein Design; Univ. of Washington, Seattle, WA (United States). Howard Hughes Medical Inst.
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); US Department of the Navy, Office of Naval Research (ONR); National Institutes of Health (NIH)
OSTI Identifier:
1335049
Alternate Identifier(s):
OSTI ID: 1379621
Grant/Contract Number:  
AC02-05CH11231; N00014-14-1-0757
Resource Type:
Journal Article: Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 52; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; computational protein design; noncanonical amino acids; metalloproteins; protein self-assembly

Citation Formats

Mills, Jeremy H., Sheffler, William, Ener, Maraia E., Almhjell, Patrick J., Oberdorfer, Gustav, Pereira, José Henrique, Parmeggiani, Fabio, Sankaran, Banumathi, Zwart, Peter H., and Baker, David. Computational design of a homotrimeric metalloprotein with a trisbipyridyl core. United States: N. p., 2016. Web. doi:10.1073/pnas.1600188113.
Mills, Jeremy H., Sheffler, William, Ener, Maraia E., Almhjell, Patrick J., Oberdorfer, Gustav, Pereira, José Henrique, Parmeggiani, Fabio, Sankaran, Banumathi, Zwart, Peter H., & Baker, David. Computational design of a homotrimeric metalloprotein with a trisbipyridyl core. United States. doi:10.1073/pnas.1600188113.
Mills, Jeremy H., Sheffler, William, Ener, Maraia E., Almhjell, Patrick J., Oberdorfer, Gustav, Pereira, José Henrique, Parmeggiani, Fabio, Sankaran, Banumathi, Zwart, Peter H., and Baker, David. Thu . "Computational design of a homotrimeric metalloprotein with a trisbipyridyl core". United States. doi:10.1073/pnas.1600188113.
@article{osti_1335049,
title = {Computational design of a homotrimeric metalloprotein with a trisbipyridyl core},
author = {Mills, Jeremy H. and Sheffler, William and Ener, Maraia E. and Almhjell, Patrick J. and Oberdorfer, Gustav and Pereira, José Henrique and Parmeggiani, Fabio and Sankaran, Banumathi and Zwart, Peter H. and Baker, David},
abstractNote = {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.},
doi = {10.1073/pnas.1600188113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 52,
volume = 113,
place = {United States},
year = {Thu Dec 08 00:00:00 EST 2016},
month = {Thu Dec 08 00:00:00 EST 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1073/pnas.1600188113

Citation Metrics:
Cited by: 5 works
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Works referenced in this record:

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunk�czi, G�bor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925