ArticleProceedings of the National Academy of Sciences of the United States of America2012
A fundamental protein property, thermodynamic stability, revealed solely from large-scale measurements of protein function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers.
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Who cites it
149 citing papers in PubMed.
- Synthetic Regulatory Genomics.Annual review of genomics and human genetics · 2026Review
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
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- Optimal sequencing depth for measuring the concentrations of molecular barcodes.Nucleic acids research · 2025Article
- Epistatic hotspots organize antibody fitness landscape and boost evolvability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- MMRT: MultiMut Recursive Tree for predicting functional effects of high-order protein variants from low-order variants.Computational and structural biotechnology journal · 2025Article
- Epitope mapping via in vitro deep mutational scanning methods and its applications.The Journal of biological chemistry · 2025Review
- A methodology for calculating the rarity of diverse proteins based on functional specificity and thermodynamic stability.PloS one · 2025Article
- Structural and energetic analysis of stabilizing indel mutations.bioRxiv : the preprint server for biology · 2024Article
- Inference and design of antibody specificity: From experiments to models and back.PLoS computational biology · 2024Article
- Molecular characterization, expression and in-silico analysis of fibrinogen-related protein 1 (frep1) in malaria vector Anopheles stephensi.Molecular biology reports · 2024Article
- popDMS infers mutation effects from deep mutational scanning data.Bioinformatics (Oxford, England) · 2024Article
- Scalable approaches for generating, validating and incorporating data from high-throughput functional assays to improve clinical variant classification.Human genetics · 2024Article
- Unsupervised modeling of mutational landscapes of adeno-associated viruses viability.BMC bioinformatics · 2024Article
- Functional effects of mutations in proteins can be predicted and interpreted by guided selection of sequence covariation information.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Network of epistatic interactions in an enzyme active site revealed by large-scale deep mutational scanning.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Inference of annealed protein fitness landscapes with AnnealDCA.PLoS computational biology · 2024Article
89 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors.
Funding
Abstract
The ability of a protein to carry out a given function results from fundamental physicochemical properties that include the protein's structure, mechanism of action, and thermodynamic stability. Traditional approaches to study these properties have typically required the direct measurement of the property of interest, oftentimes a laborious undertaking. Although protein properties can be probed by mutagenesis, this approach has been limited by its low throughput. Recent technological developments have enabled the rapid quantification of a protein's function, such as binding to a ligand, for numerous variants of that protein. Here, we measure the ability of 47,000 variants of a WW domain to bind to a peptide ligand and use these functional measurements to identify stabilizing mutations without directly assaying stability. Our approach is rooted in the well-established concept that protein function is closely related to stability. Protein function is generally reduced by destabilizing mutations, but this decrease can be rescued by stabilizing mutations. Based on this observation, we introduce partner potentiation, a metric that uses this rescue ability to identify stabilizing mutations, and identify 15 candidate stabilizing mutations in the WW domain. We tested six candidates by thermal denaturation and found two highly stabilizing mutations, one more stabilizing than any previously known mutation. Thus, physicochemical properties such as stability are latent within these large-scale protein functional data and can be revealed by systematic analysis. This approach should allow other protein properties to be discovered.
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