ArticleProteins2009
Multi-constraint computational design suggests that native sequences of germline antibody H3 loops are nearly optimal for conformational flexibility.
Article in Proteins, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Defining and Studying B Cell Receptor and TCR Interactions.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Conformational plasticity of the HIV-1 gp41 immunodominant region is recognized by multiple non-neutralizing antibodies.Communications biology · 2022Article
- Selective Recognition of Carbohydrate Antigens by Germline Antibodies Isolated from AID Knockout Mice.Journal of the American Chemical Society · 2022Article
- Protein Engineering: Advances in Phage Display for Basic Science and Medical Research.Biochemistry. Biokhimiia · 2022Review
- Modeling Immunity with Rosetta: Methods for Antibody and Antigen Design.Biochemistry · 2021Review
- Design Strategy to Create Antibody Mimetics Harbouring Immobilised Complementarity Determining Region Peptides for Practical Use.Scientific reports · 2020Article
- Local and Global Rigidification Upon Antibody Affinity Maturation.Frontiers in molecular biosciences · 2020Article
- Structure and Dynamics of Stacking Interactions in an Antibody Binding Site.Biochemistry · 2019Article
- Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The Unusual Genetics and Biochemistry of Bovine Immunoglobulins.Advances in immunology · 2018Article
- Characterizing the Diversity of the CDR-H3 Loop Conformational Ensembles in Relationship to Antibody Binding Properties.Frontiers in immunology · 2018Article
- Repertoire Analysis of Antibody CDR-H3 Loops Suggests Affinity Maturation Does Not Typically Result in Rigidification.Frontiers in immunology · 2018Article
- Antibody-Based Protective Immunity against Helminth Infections: Antibody Phage Display Derived Antibodies against BmR1 Antigen.International journal of molecular sciences · 2017Article
- Article
- A generalized quantitative antibody homeostasis model: regulation of B-cell development by BCR saturation and novel insights into bone marrow function.Clinical & translational immunology · 2017Article
- Accurate Structure Prediction of CDR H3 Loops Enabled by a Novel Structure-Based C-Terminal Constraint.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.EBioMedicine · 2015Article
- Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences.PLoS computational biology · 2015Article
- Rigidity Emerges during Antibody Evolution in Three Distinct Antibody Systems: Evidence from QSFR Analysis of Fab Fragments.PLoS computational biology · 2015Article
- Structure of the apo anti-influenza CH65 Fab.Acta crystallographica. Section F, Structural biology communications · 2015Article
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2 authors.
Funding
Abstract
The limited size of the germline antibody repertoire has to recognize a far larger number of potential antigens. The ability of a single antibody to bind multiple ligands due to conformational flexibility in the antigen-binding site can significantly enlarge the repertoire. Among the six complementarity determining regions (CDRs) that generally comprise the binding site, the CDR H3 loop is particularly variable. Computational protein design studies showed that predicted low energy sequences compatible with a given backbone structure often have considerable similarity to the corresponding native sequences of naturally occurring proteins, indicating that native protein sequences are close to optimal for their structures. Here, we take a step forward to determine whether conformational flexibility, believed to play a key functional role in germline antibodies, is also central in shaping their native sequence. In particular, we use a multi-constraint computational design strategy, along with the Rosetta scoring function, to propose that the native sequences of CDR H3 loops from germline antibodies are nearly optimal for conformational flexibility. Moreover, we find that antibody maturation may lead to sequences with a higher degree of optimization for a single conformation, while disfavoring sequences that are intrinsically flexible. In addition, this computational strategy allows us to predict mutations in the CDR H3 loop to stabilize the antigen-bound conformation, a computational mimic of affinity maturation, that may increase antigen binding affinity by preorganizing the antigen binding loop. In vivo affinity maturation data are consistent with our predictions. The method described here can be useful to design antibodies with higher selectivity and affinity by reducing conformational diversity.
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