Principles for designing ideal protein structures
Open accessAbstract
Unlike random heteropolymers, natural proteins fold into unique ordered structures. Understanding how these are encoded in amino-acid sequences is complicated by energetically unfavourable non-ideal features--for example kinked α-helices, bulged β-strands, strained loops and buried polar groups--that arise in proteins from evolutionary selection for biological function or from neutral drift. Here we describe an approach to designing ideal protein structures stabilized by completely consistent local and non-local interactions. The approach is based on a set of rules relating secondary structure patterns to protein tertiary motifs, which make possible the design of funnel-shaped protein folding energy landscapes leading into the target folded state. Guided by these rules, we designed sequences predicted to fold into ideal protein structures consisting of α-helices, β-strands and minimal loops. Designs for five different topologies were found to be monomeric and very stable and to adopt structures in solution nearly identical to the computational models. These results illuminate how the folding funnels of natural proteins arise and provide the foundation for engineering a new generation of functional proteins free from natural evolution.
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Using fragment assembly, piecewise fragment assembly and helical extension, the authors designed a large set of miniproteins that ranged in length from 50 to 65 amino acids and contained larger hydrophobic cores than previous miniprotein scaffold libraries.
“Using fragment assembly7, piecewise fragment assembly8 and helical extension9, we designed a large set of miniproteins that ranged in length from 50 to 65 amino acids and contained larger hydrophobic cores than previous miniprotein scaffold libraries1.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [7]
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Self-citation
- Authors
- Koga, N., Tatsumi-Koga, R., Liu, G., Xiao, R., Acton, T. B., Montelione, G. T., & Baker, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Montelione, Gaetano T.
- Baker, David
- Venue
- Nature
- Published
- 2012-11
- Volume
- 491
- Issue
- 7423
- Pages
- 222-227
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3705962
- OpenAlex
- W2121627241
- Cited by
- 564
- References
- 71
- Citations by year
- 2026: 30 · 2025: 25 · 2024: 36 · 2023: 36 · 2022: 48 · 2021: 50 · 2020: 52 · 2019: 40 · 2018: 25 · 2017: 35 · 2016: 51 · 2015: 46 · 2014: 48 · 2013: 39 · 2012: 3
- FWCI
- 17.38
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (U54GM094597)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- protein design, folding funnel, alpha-helix, beta-strand, sequence design, protein stability
- MeSH terms
- Computer Simulation, Models, Molecular, Proteins, Thermodynamics, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Folding, Protein Stability
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