ArticleGenetics2021
Ensemble epistasis: thermodynamic origins of nonadditivity between mutations.
Article in Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Amplicon/Protein Bead Display enables quantitativebioRxiv : the preprint server for biology · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.Nature ecology & evolution · 2026Article
- Selective control of ligand binding through a distal mutation that alters the protein native ensemble.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.bioRxiv : the preprint server for biology · 2025Article
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- ACOCMPMI: An Ant Colony Optimization Algorithm Based on Composite Multiscale Part Mutual Information for Detecting Epistatic Interactions.Human mutation · 2025Article
- Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.Nature communications · 2023Article
- Identification of a covert evolutionary pathway between two protein folds.Nature communications · 2023Article
- Decoupling epistasis mechanisms in biomacromolecules.Biophysical journal · 2023Article
- Disentangling contact and ensemble epistasis in a riboswitch.Biophysical journal · 2023Article
- Ensemble origins and distance-dependence of long-range mutational effects in proteins.iScience · 2022Article
- Evolution avoids a pathological stabilizing interaction in the immune protein S100A9.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Epistatic drift causes gradual decay of predictability in protein evolution.Science (New York, N.Y.) · 2022Article
- High throughput and quantitative enzymology in the genomic era.Current opinion in structural biology · 2021Review
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Authors and funding
3 authors.
Funding
Abstract
Epistasis-when mutations combine nonadditively-is a profoundly important aspect of biology. It is often difficult to understand its mechanistic origins. Here, we show that epistasis can arise from the thermodynamic ensemble, or the set of interchanging conformations a protein adopts. Ensemble epistasis occurs because mutations can have different effects on different conformations of the same protein, leading to nonadditive effects on its average, observable properties. Using a simple analytical model, we found that ensemble epistasis arises when two conditions are met: (1) a protein populates at least three conformations and (2) mutations have differential effects on at least two conformations. To explore the relative magnitude of ensemble epistasis, we performed a virtual deep-mutational scan of the allosteric Ca2+ signaling protein S100A4. We found that 47% of mutation pairs exhibited ensemble epistasis with a magnitude on the order of thermal fluctuations. We observed many forms of epistasis: magnitude, sign, and reciprocal sign epistasis. The same mutation pair could even exhibit different forms of epistasis under different environmental conditions. The ubiquity of thermodynamic ensembles in biology and the pervasiveness of ensemble epistasis in our dataset suggests that it may be a common mechanism of epistasis in proteins and other macromolecules.
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