ArticleNature chemistry2023
How synonymous mutations alter enzyme structure and function over long timescales.
Article in Nature chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 86 citations in OpenAlex.
- How soluble misfolded proteins bypass chaperones at the molecular level.Nature communications · 2023Pooled it
- A novel synonymous TSC2 mutation in a Chinese family leads to tuberous sclerosis type 2 by disrupting Normal pre-mRNA splicing.Journal, genetic engineering & biotechnology · 2026Article
- Protein entanglement misfolding influences whether proteins undergo proteasomal degradation or persist in near-native misfolded states.Nature communications · 2026Article
- Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.Biochimica et biophysica acta. Molecular cell research · 2026Review
- Synonymous mutations in essential genes infrequently produce fitness effects in human cell lines.Nucleic acids research · 2026Article
- Natively entangled proteins are linked to human disease and pathogenic mutations likely due to a greater misfolding propensity.bioRxiv : the preprint server for biology · 2026Article
- Detecting misfolded non-covalent lasso entanglements in protein structures, simulation trajectories, and mass spectrometry data.bioRxiv : the preprint server for biology · 2026Article
- Native entanglement misfolding contributes to age-associated structural changebioRxiv : the preprint server for biology · 2026Article
- A widespread protein misfolding mechanism is differentially rescued in vitro by chaperones based on gene essentiality.Nature communications · 2025Article
- Decoding protein dynamics with limited proteolysis coupled to mass spectrometry: A comprehensive review.Journal of pharmaceutical analysis · 2025Review
- mRNA Cancer Vaccines: From Pandemic Paradigm to Personalized Oncology Therapeutics.Cancer innovation · 2025Review
- Association of IL12RB2, RORC, and class II HLA polymorphisms with severe erythema multiforme of regorafenib in Japanese patients with colorectal cancer.Cancer chemotherapy and pharmacology · 2025Article
- Therapeutic implications of synonymous gene recoding: insights into mechanisms controlling protein biogenesis and activity.Protein & cell · 2025Article
- DRP-PSM: Multi-Level Feature Integration Reveals Hierarchical Contributions to Pathogenic Synonymous Mutation Prediction.ACS omega · 2025Article
- Properties Governing Native State Entanglements and Relationships to Protein Function.Journal of molecular biology · 2025Article
- A widespread protein misfolding mechanism is differentially rescued by chaperones based on gene essentiality.bioRxiv : the preprint server for biology · 2025Article
- Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles.Science advances · 2025Article
- Pathway regulation mechanism by cotranslational protein folding.Communications chemistry · 2025Article
- Cell type-specific purifying selection of synonymous mitochondrial DNA variation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- AlphaLasso-a web server to identify loop and lasso motifs in 3D structure of biopolymers.Nucleic acids research · 2025Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The specific activity of enzymes can be altered over long timescales in cells by synonymous mutations that alter a messenger RNA molecule's sequence but not the encoded protein's primary structure. How this happens at the molecular level is unknown. Here, we use multiscale modelling of three Escherichia coli enzymes (type III chloramphenicol acetyltransferase, D-alanine-D-alanine ligase B and dihydrofolate reductase) to understand experimentally measured changes in specific activity due to synonymous mutations. The modelling involves coarse-grained simulations of protein synthesis and post-translational behaviour, all-atom simulations to test robustness and quantum mechanics/molecular mechanics calculations to characterize enzymatic function. We show that changes in codon translation rates induced by synonymous mutations cause shifts in co-translational and post-translational folding pathways that kinetically partition molecules into subpopulations that very slowly interconvert to the native, functional state. Structurally, these states resemble the native state, with localized misfolding near the active sites of the enzymes. These long-lived states exhibit reduced catalytic activity, as shown by their increased activation energies for the reactions they catalyse.
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Registered trials
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.