ArticleProceedings of the National Academy of Sciences of the United States of America2010
Engineering a protein-protein interface using a computationally designed library.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 72 citations in OpenAlex.
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- Optimization of a sarbecovirus llama nanobody-antigen binding interface via a combined computational and phage display protein engineering approach.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.bioRxiv : the preprint server for biology · 2024Article
- GGAssembler: Precise and economical design and synthesis of combinatorial mutation libraries.Protein science : a publication of the Protein Society · 2024Article
- Targeting Ras with protein engineering.Oncotarget · 2023Review
- Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022Review
- Activation of E6AP/UBE3A-Mediated Protein Ubiquitination and Degradation Pathways by a Cyclic γ-AA Peptide.Journal of medicinal chemistry · 2022Article
- PyRosetta Jupyter Notebooks Teach Biomolecular Structure Prediction and Design.Biophysicist (Rockville, Md.) · 2021Article
- Computational design and experimental optimization of protein binders with prospects for biomedical applications.Protein engineering, design & selection : PEDS · 2021Review
- Enhancing the promiscuity of a member of the Caspase protease family by rational design.Proteins · 2020Article
- Enhancing fragment-based protein structure prediction by customising fragment cardinality according to local secondary structure.BMC bioinformatics · 2020Article
- Measuring Intrinsic Disorder and Tracking Conformational Transitions Using Rosetta ResidueDisorder.The journal of physical chemistry. B · 2019Article
- Rapid and accurate structure-based therapeutic peptide design using GPU accelerated thermodynamic integration.Proteins · 2019Article
- SKEMPI 2.0: an updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation.Bioinformatics (Oxford, England) · 2019Article
- Rosetta FunFolDes - A general framework for the computational design of functional proteins.PLoS computational biology · 2018Article
- Comparing side chain packing in soluble proteins, protein-protein interfaces, and transmembrane proteins.Proteins · 2018Article
- RosettaAntibodyDesign (RAbD): A general framework for computational antibody design.PLoS computational biology · 2018Article
- A cyber-linked undergraduate research experience in computational biomolecular structure prediction and design.PLoS computational biology · 2017Article
- Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design.Methods in molecular biology (Clifton, N.J.) · 2017Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Computational algorithms for protein design can sample large regions of sequence space, but suffer from undersampling of conformational space and energy function inaccuracies. Experimental screening of combinatorial protein libraries avoids the need for accurate energy functions, but has limited access to vast amounts of sequence space. Here, we test if these two traditionally alternative, but potentially complementary approaches can be combined to design a variant of the ubiquitin-ligase E6AP that will bind to a nonnatural partner, the NEDD8-conjugating enzyme Ubc12. Three E6AP libraries were constructed: (i) a naive library in which all 20 amino acids were allowed at every position on the target-binding surface of E6AP (13 positions), (ii) a semidirected library that varied the same residue positions as in the naive library but disallowed mutations computationally predicted to destabilize E6AP, and (iii) a directed library that used docking and sequence optimization simulations to identify mutations predicted to be favorable for binding Ubc12. Both of the directed libraries showed > 30-fold enrichment over the naive library after the first round of screening with a split-dihydrofolate reductase complementation assay and produced multiple tight binders (K(d) < 100 nM) after four rounds of selection. Four rounds of selection with the naive library failed to produce any binders with K(d)'s lower than 50 μM. These results indicate that protein design simulations can be used to create directed libraries that are enriched in tight binders and that in some cases it is sufficient to computationally screen for well-folded sequences without explicit binding calculations.
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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.