ArticleProceedings of the National Academy of Sciences of the United States of America2002
Combining computational and experimental screening for rapid optimization of protein properties.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 130 citations in OpenAlex.
- Integrating Computational Design and Experimental Approaches for Next-Generation Biologics.Biomolecules · 2024Review
- Advances in ligand-specific biosensing for structurally similar molecules.Cell systems · 2023Review
- Comparison of Rosetta flexible-backbone computational protein design methods on binding interactions.Proteins · 2020Article
- Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Structure-based design of combinatorial mutagenesis libraries.Protein science : a publication of the Protein Society · 2015Article
- SwiftLib: rapid degenerate-codon-library optimization through dynamic programming.Nucleic acids research · 2015Article
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- The genetic code constrains yet facilitates Darwinian evolution.Nucleic acids research · 2013Article
- Structure-based redesign of the binding specificity of anti-apoptotic Bcl-x(L).Journal of molecular biology · 2013Article
- Improving the thermostability of alpha-amylase by combinatorial coevolving-site saturation mutagenesis.BMC bioinformatics · 2012Article
- Predictive Bcl-2 family binding models rooted in experiment or structure.Journal of molecular biology · 2012Article
- Designing specific protein-protein interactions using computation, experimental library screening, or integrated methods.Protein science : a publication of the Protein Society · 2012Review
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- Complex recombination patterns arising during geminivirus coinfections preserve and demarcate biologically important intra-genome interaction networks.PLoS pathogens · 2011Article
- Assessment of flexible backbone protein design methods for sequence library prediction in the therapeutic antibody Herceptin-HER2 interface.Protein science : a publication of the Protein Society · 2011Article
- Experimental library screening demonstrates the successful application of computational protein design to large structural ensembles.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Engineering a protein-protein interface using a computationally designed library.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Conformational diversity and computational enzyme design.Current opinion in chemical biology · 2010Review
- Protein evolution via amino acid and codon elimination.PloS one · 2010Article
- Immunotherapy of cancer.European journal of pharmacology · 2009Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We present a combined computational and experimental method for the rapid optimization of proteins. Using beta-lactamase as a test case, we redesigned the active site region using our Protein Design Automation technology as a computational screen to search the entire sequence space. By eliminating sequences incompatible with the protein fold, Protein Design Automation rapidly reduced the number of sequences to a size amenable to experimental screening, resulting in a library of approximately equal 200,000 mutants. These were then constructed and experimentally screened to select for variants with improved resistance to the antibiotic cefotaxime. In a single round, we obtained variants exhibiting a 1,280-fold increase in resistance. To our knowledge, all of the mutations were novel, i.e., they have not been identified as beneficial by random mutagenesis or DNA shuffling or seen in any of the naturally occurring TEM beta-lactamases, the most prevalent type of Gram-negative beta-lactamases. This combined approach allows for the rapid improvement of any property that can be screened experimentally and provides a powerful broadly applicable tool for protein engineering.
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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.