In silico evolution of globular protein folds from random sequences
Open accessPublished version of a preprint
Abstract
The origin and evolution of protein folds are among the most challenging, long-standing problems in biology. We developed Protein Fold Evolution Simulator (PFES), a computational approach that simulates evolution of globular folds from random amino acid sequences with atomistic details. PFES introduces random mutations in a population of protein sequences, evaluates the effect of mutations on protein structure, and selects a new set of proteins for further evolution. Iteration of this process allows tracking the evolutionary trajectory of a changing protein fold that evolves under selective pressure for protein fold stability, interaction with other proteins, or other features shaping the fitness landscape. We employed PFES to show how stable, globular protein folds could evolve from random amino acid sequences as monomers or in complexes with other proteins. The simulations reproduce the evolution of many simple folds of natural proteins as well as emergence of distinct folds not known to exist in nature. We show that evolution of small globular protein folds from random sequences, on average, takes 1.15 to 3 amino acid replacements per site, depending on the population size, with some simulations yielding stable folds after as few as 0.2 replacements per site. These values are lower than the characteristic numbers of replacements in conserved proteins during the time since the Last Universal Common Ancestor, suggesting that simple protein folds can evolve from random sequences relatively easily and quickly. PFES tracks the complete evolutionary history from simulations and can be used to test hypotheses on protein fold evolution.
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Self-citation
- Authors
- Sahakyan, H., Babajanyan, S. G., Wolf, Y. I., & Koonin, E. V.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Sahakyan, Harutyun
- Koonin, Eugene V.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2025-06-30
- Volume
- 122
- Issue
- 27
- Pages
- e2509015122-e2509015122
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC12260532
- OpenAlex
- W4411789582
- Cited by
- 15
- References
- 79
- Citations by year
- 2026: 8 · 2025: 7
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- HHS | NIH (Intramural Research Program)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- protein fold evolution, globular proteins, in silico evolution, protein stability, protein-protein interaction, fitness landscape, evolutionary trajectories, last universal common ancestor, protein folding
- MeSH terms
- Amino Acid Sequence, Computer Simulation, Models, Molecular, Mutation, Proteins, Protein Folding, Evolution, Molecular
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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