ArticleProceedings of the National Academy of Sciences of the United States of America2009
Computational design of ligand binding is not a solved problem.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 101 citations in OpenAlex.
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- De Novo Design of Proteins That Bind Naphthalenediimides, Powerful Photooxidants with Tunable Photophysical Properties.Journal of the American Chemical Society · 2025Article
- De novo design of drug-binding proteins with predictable binding energy and specificity.Science (New York, N.Y.) · 2024Article
- Article
- Retracing the evolution of a modern periplasmic binding protein.Protein science : a publication of the Protein Society · 2023Article
- Subcellular Localization Defects Characterize Ribose-Binding Mutant Proteins with New Ligand Properties in Escherichia coli.Applied and environmental microbiology · 2022Article
- Ribose-Binding Protein Mutants With Improved Interaction Towards the Non-natural Ligand 1,3-Cyclohexanediol.Frontiers in bioengineering and biotechnology · 2021Article
- New computational protein design methods for de novo small molecule binding sites.PLoS computational biology · 2020Article
- Identification and Analysis of Natural Building Blocks for Evolution-Guided Fragment-Based Protein Design.Journal of molecular biology · 2020Article
- NMR Analysis of Apo Glutamine-Binding Protein Exposes Challenges in the Study of Interdomain Dynamics.Angewandte Chemie (International ed. in English) · 2019Article
- Computational redesign of the Escherichia coli ribose-binding protein ligand binding pocket for 1,3-cyclohexanediol and cyclohexanol.Scientific reports · 2019Article
- Accurate Estimation of Ligand Binding Affinity Changes upon Protein Mutation.ACS central science · 2018Article
- Redesign of LAOBP to bind novel l-amino acid ligands.Protein science : a publication of the Protein Society · 2018Article
- Osmolyte-Like Stabilizing Effects of Low GdnHCl Concentrations on d-Glucose/d-Galactose-Binding Protein.International journal of molecular sciences · 2017Article
- Complete alanine scanning of the Escherichia coli RbsB ribose binding protein reveals residues important for chemoreceptor signaling and periplasmic abundance.Scientific reports · 2017Article
- A growth- and bioluminescence-based bioreporter for the in vivo detection of novel biocatalysts.Microbial biotechnology · 2017Article
- CSAR Benchmark Exercise 2013: Evaluation of Results from a Combined Computational Protein Design, Docking, and Scoring/Ranking Challenge.Journal of chemical information and modeling · 2016Article
- Computational design of enzyme-ligand binding using a combined energy function and deterministic sequence optimization algorithm.Journal of molecular modeling · 2015Article
- Insertion of a xylanase in xylose binding protein results in a xylose-stimulated xylanase.Biotechnology for biofuels · 2015Article
- Escherichia [corrected] coli ribose binding protein based bioreporters revisited.Scientific reports · 2014Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Computational design has been very successful in recent years: multiple novel ligand binding proteins as well as enzymes have been reported. We wanted to know in molecular detail how precise the predictions of the interactions of protein and ligands are. Therefore, we performed a structural analysis of a number of published receptors designed onto the periplasmic binding protein scaffold that were reported to bind to the new ligands with nano- to micromolar affinities. It turned out that most of these designed proteins are not suitable for structural studies due to instability and aggregation. However, we were able to solve the crystal structure of an arabinose binding protein designed to bind serotonin to 2.2 A resolution. While crystallized in the presence of an excess of serotonin, the protein is in an open conformation with no serotonin bound, although the side-chain conformations in the empty binding pocket are very similar to the conformations predicted. During subsequent characterization using isothermal titration calorimetry, CD, and NMR spectroscopy, no indication of binding could be detected for any of the tested designed receptors, whereas wild-type proteins bound their ligands as expected. We conclude that although the computational prediction of side-chain conformations appears to be working, it does not necessarily confer binding as expected. Hence, the computational design of ligand binding is not a solved problem and needs to be revisited.
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