ArticleNature communications2023
Designed active-site library reveals thousands of functional GFP variants.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Kozak sequences regulate gene expression in Trypanosoma brucei.Nucleic acids research · 2026Article
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- Inference and Visualization of Complex Genotype-Phenotype Maps.Molecular biology and evolution · 2026Article
- Sign Epistasis Can be Absent in Multi-peaked Landscapes With Neutral Mutations.Genome biology and evolution · 2026Article
- Biophysics-based protein language models for protein engineering.Nature methods · 2025Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Integrative biophysical characterization of molecular interactions: A case study with the sfGFP-nanobody complex.Analytical biochemistry · 2025Article
- Computationally Designed Peroxygenases That Exhibit Diverse and Selective Terpene Oxyfunctionalization.ACS catalysis · 2025Article
- Article
- Evolutionary paths that link orthogonal pairs of binding proteins.Cell systems · 2025Article
- Biophysics-based protein language models for protein engineering.bioRxiv : the preprint server for biology · 2025Article
- GGAssembler: Precise and economical design and synthesis of combinatorial mutation libraries.Protein science : a publication of the Protein Society · 2024Article
- Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering.Cell research · 2024Article
- Article
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Opportunities and challenges in design and optimization of protein function.Nature reviews. Molecular cell biology · 2024Review
- Improving the enzymatic activity and stability of N-carbamoyl hydrolase using deep learning approach.Microbial cell factories · 2024Article
- Opportunities and Challenges for Machine Learning-Assisted Enzyme Engineering.ACS central science · 2024Review
- LibGENiE - A bioinformatic pipeline for the design of information-enriched enzyme libraries.Computational and structural biotechnology journal · 2023Article
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Authors and funding
12 authors.
Funding
Abstract
Mutations in a protein active site can lead to dramatic and useful changes in protein activity. The active site, however, is sensitive to mutations due to a high density of molecular interactions, substantially reducing the likelihood of obtaining functional multipoint mutants. We introduce an atomistic and machine-learning-based approach, called high-throughput Functional Libraries (htFuncLib), that designs a sequence space in which mutations form low-energy combinations that mitigate the risk of incompatible interactions. We apply htFuncLib to the GFP chromophore-binding pocket, and, using fluorescence readout, recover >16,000 unique designs encoding as many as eight active-site mutations. Many designs exhibit substantial and useful diversity in functional thermostability (up to 96 °C), fluorescence lifetime, and quantum yield. By eliminating incompatible active-site mutations, htFuncLib generates a large diversity of functional sequences. We envision that htFuncLib will be used in one-shot optimization of activity in enzymes, binders, and other proteins.
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