ArticleProceedings of the National Academy of Sciences of the United States of America2017
Molecular ensembles make evolution unpredictable.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed.
- From possibility to precision in macromolecular ensemble prediction.Nature methods · 2026Review
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters.Nature structural & molecular biology · 2025Article
- Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains.Journal of virology · 2025Article
- Protein stability models fail to capture epistatic interactions of double point mutations.Protein science : a publication of the Protein Society · 2025Article
- The origin of mutational epistasis.European biophysics journal : EBJ · 2024Article
- The simplicity of protein sequence-function relationships.Nature communications · 2024Article
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.Nature communications · 2024Article
- Analysis of proteins in the light of mutations.European biophysics journal : EBJ · 2024Review
- Effects of selection stringency on the outcomes of directed evolution.bioRxiv : the preprint server for biology · 2024Article
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.Research square · 2024Article
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.bioRxiv : the preprint server for biology · 2024Article
- Mutational biases favor complexity increases in protein interaction networks after gene duplication.Molecular systems biology · 2024Article
- The simplicity of protein sequence-function relationships.bioRxiv : the preprint server for biology · 2024Article
- Article
- Protein folding rate evolution upon mutations.Biophysical reviews · 2023Review
- 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
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- Fitness of evolving bacterial populations is contingent on deep and shallow history but only shallow history creates predictable patterns.Proceedings. Biological sciences · 2022Article
- Three-dimensional structure-guided evolution of a ribosome with tethered subunits.Nature chemical biology · 2022Article
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2 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Evolutionary prediction is of deep practical and philosophical importance. Here we show, using a simple computational protein model, that protein evolution remains unpredictable, even if one knows the effects of all mutations in an ancestral protein background. We performed a virtual deep mutational scan-revealing the individual and pairwise epistatic effects of every mutation to our model protein-and then used this information to predict evolutionary trajectories. Our predictions were poor. This is a consequence of statistical thermodynamics. Proteins exist as ensembles of similar conformations. The effect of a mutation depends on the relative probabilities of conformations in the ensemble, which in turn, depend on the exact amino acid sequence of the protein. Accumulating substitutions alter the relative probabilities of conformations, thereby changing the effects of future mutations. This manifests itself as subtle but pervasive high-order epistasis. Uncertainty in the effect of each mutation accumulates and undermines prediction. Because conformational ensembles are an inevitable feature of proteins, this is likely universal.
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