ArticleProteins2015
Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association.
Article in Proteins, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Topological metrics as evolutionary and dynamical descriptors of conformational landscapes within protein families.PLoS computational biology · 2026Article
- Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.Journal of molecular biology · 2025Review
- Tailoring industrial enzymes for thermostability and activity evolution by the machine learning-based iCASE strategy.Nature communications · 2025Article
- 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
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Article
- Engineering gain-of-function mutants of a WW domain by dynamics and structural analysis.Protein science : a publication of the Protein Society · 2023Article
- Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.Protein science : a publication of the Protein Society · 2023Article
- Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations.eLife · 2022Article
- Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.PLoS computational biology · 2022Article
- Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity.Nature communications · 2021Article
- The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability.International journal of molecular sciences · 2021Article
- Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions.Molecular biology and evolution · 2021Article
- Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes.Journal of biomolecular structure & dynamics · 2019Article
- Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 β-lactamase.International journal of molecular sciences · 2018Article
- Coevolving residues inform protein dynamics profiles and disease susceptibility of nSNVs.PLoS computational biology · 2018Article
- Hinge-Shift Mechanism Modulates Allosteric Regulations in Human Pin1.The journal of physical chemistry. B · 2018Article
- Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity.Scientific reports · 2017Article
- Comparative Study of Elastic Network Model and Protein Contact Network for Protein Complexes: The Hemoglobin Case.BioMed research international · 2017Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Recent studies have shown that the protein interface sites between individual monomeric units in biological assemblies are enriched in disease-associated non-synonymous single nucleotide variants (nsSNVs). To elucidate the mechanistic underpinning of this observation, we investigated the conformational dynamic properties of protein interface sites through a site-specific structural dynamic flexibility metric (dfi) for 333 multimeric protein assemblies. dfi measures the dynamic resilience of a single residue to perturbations that occurred in the rest of the protein structure and identifies sites contributing the most to functionally critical dynamics. Analysis of dfi profiles of over a thousand positions harboring variation revealed that amino acid residues at interfaces have lower average dfi (31%) than those present at non-interfaces (50%), which means that protein interfaces have less dynamic flexibility. Interestingly, interface sites with disease-associated nsSNVs have significantly lower average dfi (23%) as compared to those of neutral nsSNVs (42%), which directly relates structural dynamics to functional importance. We found that less conserved interface positions show much lower dfi for disease nsSNVs as compared to neutral nsSNVs. In this case, dfi is better as compared to the accessible surface area metric, which is based on the static protein structure. Overall, our proteome-wide conformational dynamic analysis indicates that certain interface sites play a critical role in functionally related dynamics (i.e., those with low dfi values), therefore mutations at those sites are more likely to be associated with disease.
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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.