Role of backbone strain in de novo design of complex α/β protein structures
Abstract
Abstract We previously elucidated principles for designing ideal proteins with completely consistent local and non-local interactions which have enabled the design of a wide range of new αβ-proteins with four or fewer β-strands. The principles relate local backbone structures to supersecondary-structure packing arrangements of α-helices and β-strands. Here, we test the generality of the principles by employing them to design larger proteins with five- and six- stranded β-sheets flanked by α-helices. The initial designs were monomeric in solution with high thermal stability, and the nuclear magnetic resonance (NMR) structure of one was close to the design model, but for two others the order of strands in the β-sheet was swapped. Investigation into the origins of this strand swapping suggested that the global structures of the design models were more strained than the NMR structures. We incorporated explicit consideration of global backbone strain into the design methodology, and succeeded in designing proteins with the intended unswapped strand arrangements. These results illustrate the value of experimental structure determination in guiding improvement of de novo design, and the importance of consistency between local, supersecondary, and global tertiary interactions in determining protein topology. The augmented set of principles should inform the design of larger functionalmore »
- Publication Date:
- Research Org.:
- Univ. of Washington, Seattle, WA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); Japan Society for the Promotion of Science (JSPS); Japan Science and Technology Agency
- OSTI Identifier:
- 1798386
- Alternate Identifier(s):
- OSTI ID: 1816536
- Grant/Contract Number:
- R01-GM120574; 15H05592; 18H05420; JPMJPR13AD
- Resource Type:
- Published Article
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Name: Nature Communications Journal Volume: 12 Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; computational biophysics; protein design; solution-state NMR; structural biology
Citation Formats
Koga, Nobuyasu, Koga, Rie, Liu, Gaohua, Castellanos, Javier, Montelione, Gaetano T., and Baker, David. Role of backbone strain in de novo design of complex α/β protein structures. United Kingdom: N. p., 2021.
Web. doi:10.1038/s41467-021-24050-7.
Koga, Nobuyasu, Koga, Rie, Liu, Gaohua, Castellanos, Javier, Montelione, Gaetano T., & Baker, David. Role of backbone strain in de novo design of complex α/β protein structures. United Kingdom. https://doi.org/10.1038/s41467-021-24050-7
Koga, Nobuyasu, Koga, Rie, Liu, Gaohua, Castellanos, Javier, Montelione, Gaetano T., and Baker, David. Thu .
"Role of backbone strain in de novo design of complex α/β protein structures". United Kingdom. https://doi.org/10.1038/s41467-021-24050-7.
@article{osti_1798386,
title = {Role of backbone strain in de novo design of complex α/β protein structures},
author = {Koga, Nobuyasu and Koga, Rie and Liu, Gaohua and Castellanos, Javier and Montelione, Gaetano T. and Baker, David},
abstractNote = {Abstract We previously elucidated principles for designing ideal proteins with completely consistent local and non-local interactions which have enabled the design of a wide range of new αβ-proteins with four or fewer β-strands. The principles relate local backbone structures to supersecondary-structure packing arrangements of α-helices and β-strands. Here, we test the generality of the principles by employing them to design larger proteins with five- and six- stranded β-sheets flanked by α-helices. The initial designs were monomeric in solution with high thermal stability, and the nuclear magnetic resonance (NMR) structure of one was close to the design model, but for two others the order of strands in the β-sheet was swapped. Investigation into the origins of this strand swapping suggested that the global structures of the design models were more strained than the NMR structures. We incorporated explicit consideration of global backbone strain into the design methodology, and succeeded in designing proteins with the intended unswapped strand arrangements. These results illustrate the value of experimental structure determination in guiding improvement of de novo design, and the importance of consistency between local, supersecondary, and global tertiary interactions in determining protein topology. The augmented set of principles should inform the design of larger functional proteins.},
doi = {10.1038/s41467-021-24050-7},
journal = {Nature Communications},
number = 1,
volume = 12,
place = {United Kingdom},
year = {Thu Jun 24 00:00:00 EDT 2021},
month = {Thu Jun 24 00:00:00 EDT 2021}
}
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