ArticleNucleic acids research2016
Localized structural frustration for evaluating the impact of sequence variants.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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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
9 citing papers in PubMed, 19 citations in OpenAlex.
- Frustration in physiology and molecular medicine.Molecular aspects of medicine · 2025Review
- Molecular annotation of G protein variants in a neurological disorder.Cell reports · 2023Article
- Local energetic frustration conservation in protein families and superfamilies.Nature communications · 2023Article
- Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations.Bioinformatics (Oxford, England) · 2021Article
- SVFX: a machine learning framework to quantify the pathogenicity of structural variants.Genome biology · 2020Article
- Leveraging protein dynamics to identify cancer mutational hotspots using 3D structures.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Insights into genetics, human biology and disease gleaned from family based genomic studies.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Review
- "Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.Scientific reports · 2018Article
- Frustration, function and folding.Current opinion in structural biology · 2018Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Population-scale sequencing is increasingly uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions of the genome. The rarity of these variants makes it challenging to evaluate their deleteriousness with conventional phenotype-genotype associations. Protein structures provide a way of addressing this challenge. Previous efforts have focused on globally quantifying the impact of SNVs on protein stability. However, local perturbations may severely impact protein functionality without strongly disrupting global stability (e.g. in relation to catalysis or allostery). Here, we describe a workflow in which localized frustration, quantifying unfavorable local interactions, is employed as a metric to investigate such effects. Using this workflow on the Protein Databank, we find that frustration produces many immediately intuitive results: for instance, disease-related SNVs create stronger changes in localized frustration than non-disease related variants, and rare SNVs tend to disrupt local interactions to a larger extent than common variants. Less obviously, we observe that somatic SNVs associated with oncogenes and tumor suppressor genes (TSGs) induce very different changes in frustration. In particular, those associated with TSGs change the frustration more in the core than the surface (by introducing loss-of-function events), whereas those associated with oncogenes manifest the opposite pattern, creating gain-of-function events.
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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.