ArticlePLoS computational biology2022
Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.
Article in PLoS computational biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 42 citations in OpenAlex.
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- Computational Identification of Potential Novel Allosteric IHF Inhibitors Using QSAR Modeling to Inhibit Plasmid-Mediated Antibiotic Resistance.International journal of molecular sciences · 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
- A protein dynamics-based deep learning model enhances predictions of fitness and epistasis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.Journal of molecular biology · 2025Review
- Statistical Physics-Based Approaches to Model the Function and Complexation of Disordered Proteins.The journal of physical chemistry. B · 2025Article
- Long-range coupling regulates stator dynamics in the bacterial flagellar motor.bioRxiv : the preprint server for biology · 2025Article
- Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.Protein science : a publication of the Protein Society · 2025Article
- Dynamics-based protein network features accurately discriminate neutral and rheostat positions.Biophysical journal · 2024Article
- Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory.Journal of chemical theory and computation · 2024Article
- Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately.Science advances · 2024Article
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- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Engineering gain-of-function mutants of a WW domain by dynamics and structural analysis.Protein science : a publication of the Protein Society · 2023Article
- 3DDPDs: describing protein dynamics for proteochemometric bioactivity prediction. A case for (mutant) G protein-coupled receptors.Journal of cheminformatics · 2023Article
- Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.Protein science : a publication of the Protein Society · 2023Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.
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