ArticleBiophysical journal2017
How Many Protein Sequences Fold to a Given Structure? A Coevolutionary Analysis.
Article in Biophysical journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- A methodology for calculating the rarity of diverse proteins based on functional specificity and thermodynamic stability.PloS one · 2025Article
- Hierarchical Analysis of Protein Structures: From Secondary Structures to Protein Units and Domains.Methods in molecular biology (Clifton, N.J.) · 2025Article
- A systematic analysis of regression models for protein engineering.PLoS computational biology · 2024Article
- Selection pressures on evolution of ribonuclease H explored with rigorous free-energy-based design.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Alternative Reading Frames are an Underappreciated Source of Protein Sequence Novelty.Journal of molecular evolution · 2023Review
- Fluid protein fold space and its implications.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Article
- A review of visualisations of protein fold networks and their relationship with sequence and function.Biological reviews of the Cambridge Philosophical Society · 2023Review
- Design of a Protein with Improved Thermal Stability by an Evolution-Based Generative Model.Angewandte Chemie (International ed. in English) · 2022Article
- Identification of novel functional mini-receptors by combinatorial screening of split-WW domains.Chemical science · 2022Article
- Allosteric Inter-Domain Contacts in Bacterial Hsp70 Are Located in Regions That Avoid Insertion and Deletion Events.International journal of molecular sciences · 2022Article
- Biological factors in the synthetic construction of overlapping genes.BMC genomics · 2021Article
- Efficient generative modeling of protein sequences using simple autoregressive models.Nature communications · 2021Article
- Insertions and deletions in the RNA sequence-structure map.Journal of the Royal Society, Interface · 2021Article
- Rosetta design with co-evolutionary information retains protein function.PLoS computational biology · 2021Article
- Exploring the sequence fitness landscape of a bridge between protein folds.PLoS computational biology · 2020Article
- Size and structure of the sequence space of repeat proteins.PLoS computational biology · 2019Article
- Design of metalloproteins and novel protein folds using variational autoencoders.Scientific reports · 2018Article
- Co-Evolutionary Fitness Landscapes for Sequence Design.Angewandte Chemie (International ed. in English) · 2018Article
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2 authors.
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Abstract
Quantifying the relationship between protein sequence and structure is key to understanding the protein universe. A fundamental measure of this relationship is the total number of amino acid sequences that can fold to a target protein structure, known as the "sequence capacity," which has been suggested as a proxy for how designable a given protein fold is. Although sequence capacity has been extensively studied using lattice models and theory, numerical estimates for real protein structures are currently lacking. In this work, we have quantitatively estimated the sequence capacity of 10 proteins with a variety of different structures using a statistical model based on residue-residue co-evolution to capture the variation of sequences from the same protein family. Remarkably, we find that even for the smallest protein folds, such as the WW domain, the number of foldable sequences is extremely large, exceeding the Avogadro constant. In agreement with earlier theoretical work, the calculated sequence capacity is positively correlated with the size of the protein, or better, the density of contacts. This allows the absolute sequence capacity of a given protein to be approximately predicted from its structure. On the other hand, the relative sequence capacity, i.e., normalized by the total number of possible sequences, is an extremely tiny number and is strongly anti-correlated with the protein length. Thus, although there may be more foldable sequences for larger proteins, it will be much harder to find them. Lastly, we have correlated the evolutionary age of proteins in the CATH database with their sequence capacity as predicted by our model. The results suggest a trade-off between the opposing requirements of high designability and the likelihood of a novel fold emerging by chance.
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