ArticleScientific reports2017
Computational predictors fail to identify amino acid substitution effects at rheostat positions.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Predicting Functional Effects of Synonymous Variants: A Systematic Review and Perspectives.Frontiers in genetics · 2019Pooled it
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- Identification of positions in human aldolase a that are neutral for apparent KArchives of biochemistry and biophysics · 2024Article
- Dynamics-based protein network features accurately discriminate neutral and rheostat positions.Biophysical journal · 2024Article
- Rheostatic contributions to protein stability can obscure a position's functional role.Protein science : a publication of the Protein Society · 2024Article
- Variant Effect Prediction in the Age of Machine Learning.Cold Spring Harbor perspectives in biology · 2024Review
- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- The intrinsically disordered transcriptional activation domain of CIITA is functionally tuneable by single substitutions: An exception or a new paradigm?Protein science : a publication of the Protein Society · 2024Article
- PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes.Database : the journal of biological databases and curation · 2023Article
- VariBench, new variation benchmark categories and data sets.Frontiers in bioinformatics · 2023Article
- FUS G559A Mutation in a Patient with a Frontotemporal Dementia-Motor Neuron Disease Compatible Syndrome: A Case Report.Journal of Alzheimer's disease reports · 2023Article
- Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations.eLife · 2022Article
- Embeddings from protein language models predict conservation and variant effects.Human genetics · 2022Article
- Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.Protein science : a publication of the Protein Society · 2022Article
- Discovering interrelated natural mutations of efflux pump KmrA from Klebsiella pneumoniae that confer increased multidrug resistance.Protein science : a publication of the Protein Society · 2022Article
- Dynamic allostery highlights the evolutionary differences between the CoV-1 and CoV-2 main proteases.Biophysical journal · 2022Article
- Structural Plasticity Is a Feature of Rheostat Positions in the Human NaInternational journal of molecular sciences · 2022Article
- Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.Protein science : a publication of the Protein Society · 2022Article
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Many computational approaches exist for predicting the effects of amino acid substitutions. Here, we considered whether the protein sequence position class - rheostat or toggle - affects these predictions. The classes are defined as follows: experimentally evaluated effects of amino acid substitutions at toggle positions are binary, while rheostat positions show progressive changes. For substitutions in the LacI protein, all evaluated methods failed two key expectations: toggle neutrals were incorrectly predicted as more non-neutral than rheostat non-neutrals, while toggle and rheostat neutrals were incorrectly predicted to be different. However, toggle non-neutrals were distinct from rheostat neutrals. Since many toggle positions are conserved, and most rheostats are not, predictors appear to annotate position conservation better than mutational effect. This finding can explain the well-known observation that predictors assign disproportionate weight to conservation, as well as the field's inability to improve predictor performance. Thus, building reliable predictors requires distinguishing between rheostat and toggle positions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.