ArticlePLoS computational biology2020
New computational protein design methods for de novo small molecule binding sites.
Article in PLoS computational biology, 2020. 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.
- A Hybrid Physics-Deep Learning Framework for Combinatorial De Novo Design of Small-Molecule Binding Proteins.bioRxiv : the preprint server for biology · 2026Article
- MAGPIE: An interactive tool for visualizing and analyzing protein-ligand interactions.Protein science : a publication of the Protein Society · 2024Article
- Controlling heme redox properties in peptide amphiphile fibers with sequence and heme loading ratio.Biophysical journal · 2024Article
- Review
- Advances in ligand-specific biosensing for structurally similar molecules.Cell systems · 2023Review
- Transcription factor-based biosensors for screening and dynamic regulation.Frontiers in bioengineering and biotechnology · 2023Review
- Advances in the Computational Design of Small-Molecule-Controlled Protein-Based Circuits for Synthetic Biology.Proceedings of the IEEE. Institute of Electrical and Electronics Engineers · 2022Article
- De novo protein fold families expand the designable ligand binding site space.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
- Recent Progress Using De Novo Design to Study Protein Structure, Design and Binding Interactions.Life (Basel, Switzerland) · 2021Review
- Re-engineering Plant Phenylpropanoid Metabolism With the Aid of Synthetic Biosensors.Frontiers in plant science · 2021Review
- New computational protein design methods for de novo small molecule binding sites.PLoS computational biology · 2020Article
- Recent advances in de novo protein design: Principles, methods, and applications.The Journal of biological chemistryReview
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2 authors.
Funding
Abstract
Protein binding to small molecules is fundamental to many biological processes, yet it remains challenging to predictively design this functionality de novo. Current state-of-the-art computational design methods typically rely on existing small molecule binding sites or protein scaffolds with existing shape complementarity for a target ligand. Here we introduce new methods that utilize pools of discrete contacts between protein side chains and defined small molecule ligand substructures (ligand fragments) observed in the Protein Data Bank. We use the Rosetta Molecular Modeling Suite to recombine protein side chains in these contact pools to generate hundreds of thousands of energetically favorable binding sites for a target ligand. These composite binding sites are built into existing scaffold proteins matching the intended binding site geometry with high accuracy. In addition, we apply pools of side chain rotamers interacting with the target ligand to augment Rosetta's conventional design machinery and improve key metrics known to be predictive of design success. We demonstrate that our method reliably builds diverse binding sites into different scaffold proteins for a variety of target molecules. Our generalizable de novo ligand binding site design method provides a foundation for versatile design of protein to interface previously unattainable molecules for applications in medical diagnostics and synthetic biology.
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