ArticleProtein science : a publication of the Protein Society2011
Assessment of flexible backbone protein design methods for sequence library prediction in the therapeutic antibody Herceptin-HER2 interface.
Article in Protein science : a publication of the Protein Society, 2011. 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.
- Generation of bright monomeric red fluorescent proteinsChemical science · 2022Article
- IsAb: a computational protocol for antibody design.Briefings in bioinformatics · 2021Article
- Ensemble-based enzyme design can recapitulate the effects of laboratory directed evolution in silico.Nature communications · 2020Article
- Comparison of Rosetta flexible-backbone computational protein design methods on binding interactions.Proteins · 2020Article
- Antibody Structure and Function: The Basis for Engineering Therapeutics.Antibodies (Basel, Switzerland) · 2019Review
- Computational design of a modular protein sense-response system.Science (New York, N.Y.) · 2019Article
- Formation of multimeric antibodies for self-delivery of active monomers.Drug delivery · 2017Article
- Pushing the Backbone in Protein-Protein Docking.Structure (London, England : 1993) · 2016Article
- Algorithms for protein design.Current opinion in structural biology · 2016Review
- Protein backbone ensemble generation explores the local structural space of unseen natural homologs.Bioinformatics (Oxford, England) · 2016Article
- Computationally Designed Bispecific Antibodies using Negative State Repertoires.Structure (London, England : 1993) · 2016Article
- AB-Bind: Antibody binding mutational database for computational affinity predictions.Protein science : a publication of the Protein Society · 2016Article
- Article
- Optimization of rotamers prior to template minimization improves stability predictions made by computational protein design.Protein science : a publication of the Protein Society · 2015Article
- Computationally designed libraries for rapid enzyme stabilization.Protein engineering, design & selection : PEDS · 2014Article
- A flexible docking approach for prediction of T cell receptor-peptide-MHC complexes.Protein science : a publication of the Protein Society · 2013Article
- Computational protein design quantifies structural constraints on amino acid covariation.PLoS computational biology · 2013Article
- Computer-aided antibody design.Protein engineering, design & selection : PEDS · 2012Review
- Multistate approaches in computational protein design.Protein science : a publication of the Protein Society · 2012Review
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Authors and funding
3 authors.
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Abstract
Computational protein design methods can complement experimental screening and selection techniques by predicting libraries of low-energy sequences compatible with a desired structure and function. Incorporating backbone flexibility in computational design allows conformational adjustments that should broaden the range of predicted low-energy sequences. Here, we evaluate computational predictions of sequence libraries from different protocols for modeling backbone flexibility using the complex between the therapeutic antibody Herceptin and its target human epidermal growth factor receptor 2 (HER2) as a model system. Within the program RosettaDesign, three methods are compared: The first two use ensembles of structures generated by Monte Carlo protocols for near-native conformational sampling: kinematic closure (KIC) and backrub, and the third method uses snapshots from molecular dynamics (MD) simulations. KIC or backrub methods were better able to identify the amino acid residues experimentally observed by phage display in the Herceptin-HER2 interface than MD snapshots, which generated much larger conformational and sequence diversity. KIC and backrub, as well as fixed backbone simulations, captured the key mutation Asp98Trp in Herceptin, which leads to a further threefold affinity improvement of the already subnanomolar parental Herceptin-HER2 interface. Modeling subtle backbone conformational changes may assist in the design of sequence libraries for improving the affinity of antibody-antigen interfaces and could be suitable for other protein complexes for which structural information is available.
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