ArticleJournal of structural biology2014
Computational design of protein-small molecule interfaces.
Article in Journal of structural biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Modeling reveals the strength of weak interactions in stacked-ring assembly.Biophysical journal · 2024Article
- Sunsetting Binding MOAD with its last data update and the addition of 3D-ligand polypharmacology tools.Scientific reports · 2023Article
- Computational redesign of a fluorogen activating protein with Rosetta.PLoS computational biology · 2021Article
- Step-by-step design of proteins for small molecule interaction: A review on recent milestones.Protein science : a publication of the Protein Society · 2021Review
- New computational protein design methods for de novo small molecule binding sites.PLoS computational biology · 2020Article
- Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme.Protein science : a publication of the Protein Society · 2018Article
- Article
- Computational design of membrane proteins using RosettaMembrane.Protein science : a publication of the Protein Society · 2018Article
- Web-accessible molecular modeling with Rosetta: The Rosetta Online Server that Includes Everyone (ROSIE).Protein science : a publication of the Protein Society · 2018Article
- Protocols for Molecular Modeling with Rosetta3 and RosettaScripts.Biochemistry · 2016Review
- Rosetta and the Design of Ligand Binding Sites.Methods in molecular biology (Clifton, N.J.) · 2016Article
- AbDesign: An algorithm for combinatorial backbone design guided by natural conformations and sequences.Proteins · 2015Article
- Coupling Protein Side-Chain and Backbone Flexibility Improves the Re-design of Protein-Ligand Specificity.PLoS computational biology · 2015Article
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Authors and funding
6 authors.
Funding
Abstract
The computational design of proteins that bind small molecule ligands is one of the unsolved challenges in protein engineering. It is complicated by the relatively small size of the ligand which limits the number of intermolecular interactions. Furthermore, near-perfect geometries between interacting partners are required to achieve high binding affinities. For apolar, rigid small molecules the interactions are dominated by short-range van der Waals forces. As the number of polar groups in the ligand increases, hydrogen bonds, salt bridges, cation-π, and π-π interactions gain importance. These partial covalent interactions are longer ranged, and additionally, their strength depends on the environment (e.g. solvent exposure). To assess the current state of protein-small molecule interface design, we benchmark the popular computer algorithm Rosetta on a diverse set of 43 protein-ligand complexes. On average, we achieve sequence recoveries in the binding site of 59% when the ligand is allowed limited reorientation, and 48% when the ligand is allowed full reorientation. When simulating the redesign of a protein binding site, sequence recovery among residues that contribute most to binding was 52% when slight ligand reorientation was allowed, and 27% when full ligand reorientation was allowed. As expected, sequence recovery correlates with ligand displacement.
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