Computational Design of a Single Amino Acid Sequence that Can Switch between Two Distinct Protein Folds
Abstract
The functions of many proteins are mediated by specific conformational changes, and therefore the ability to design primary sequences capable of secondary and tertiary changes is an important step toward the creation of novel functional proteins. To this end, we have developed an algorithm that can optimize a single amino acid sequence for multiple target structures. The algorithm consists of an outer loop, in which sequence space is sampled by a Monte Carlo search with simulated annealing, and an inner loop, in which the effect of a given mutation is evaluated on the various target structures by using the rotamer packing routine and composite energy function of the protein design software, RosettaDesign. We have experimentally tested the method by designing a peptide, Sw2, which can be switched from a 2Cys-2His zinc finger-like fold to a trimeric coiled-coil fold, depending upon the pH or the presence of transition metals. Physical characterization of Sw2 confirms that it is able to reversibly adopt each intended target fold.
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Achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.
“While this has been accomplished in a number of cases,18−31 achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [19]
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- Authors
- Ambroggio, X. I., & Kuhlman, B.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Kuhlman, Brian
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-01-04
- Volume
- 128
- Issue
- 4
- Pages
- 1154-1161
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2046994420
- Cited by
- 200
- References
- 0
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 13 · 2022: 4 · 2021: 15 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 7 · 2015: 7 · 2014: 6 · 2013: 7 · 2012: 7
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- protein design, conformational change, Monte Carlo simulated annealing, composite energy function, pH-dependent folding, peptide design
- MeSH terms
- Algorithms, Amino Acid Sequence, Kinetics, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Proteins, Thermodynamics, Zinc Fingers, Protein Folding
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