ArticleProceedings of the National Academy of Sciences of the United States of America2015
Protein folding and binding can emerge as evolutionary spandrels through structural coupling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed.
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- A simple model captures key characteristics of biological non-deterministic genotype-phenotype maps.PLoS computational biology · 2026Article
- Enhancing mutation impact prediction in protein-protein interactions through interpretable graph-based multi-level feature interactions.Bioinformatics (Oxford, England) · 2026Article
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- Antioxidant, antiaging and mitochondrial protective effects of JadeAging inFrontiers in pharmacology · 2025Article
- Concepts and Methods for Predicting Viral Evolution.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Zepyros: a webserver to evaluate the shape complementarity of protein-protein interfaces.Bioinformatics advances · 2025Article
- Concepts and methods for predicting viral evolution.bioRxiv : the preprint server for biology · 2024Article
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- Cellular location shapes quaternary structure of enzymes.Nature communications · 2024Article
- An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes.Molecular biology and evolution · 2023Article
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity.Scientific reports · 2022Article
- Mechanisms of protein evolution.Protein science : a publication of the Protein Society · 2022Review
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- MAVE-NN: learning genotype-phenotype maps from multiplex assays of variant effect.Genome biology · 2022Article
- Public Immunity: Evolutionary Spandrels for Pathway-Amplifying Protective Antibodies.Frontiers in immunology · 2021Review
- Article
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2 authors.
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Abstract
Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and gene regulation. These interactions often evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic). Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between folding and binding--the fact that most proteins can only bind their targets when folded--gives rise to an evolutionary coupling between the traits of folding stability and binding strength. Using a biophysical and evolutionary model, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if its misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutational events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of how natural and engineered proteins evolve under selective pressure.
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