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    Backbone flexibility of CDR3 and immune recognition of antigens

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    Authors
    Haidar, Jaafar N.
    Zhu, Wei
    Lypowy, Jacqueline
    Pierce, Brian G.
    Bari, Amtul
    Persaud, Kris
    Luna, Xenia
    Snavely, Marshall
    Ludwig, Dale
    Weng, Zhiping
    UMass Chan Affiliations
    Program in Bioinformatics and Integrative Biology
    Document Type
    Journal Article
    Publication Date
    2014-04-03
    Keywords
    Complementarity Determining Regions
    Databases, Protein
    Entropy
    Immunoglobulins
    Protein Binding
    Protein Conformation
    Protein Structure, Secondary
    Receptors, Antigen, T-Cell
    Surface Plasmon Resonance
    Biochemistry, Biophysics, and Structural Biology
    Bioinformatics
    Computational Biology
    Integrative Biology
    Systems Biology
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    http://dx.doi.org/10.1016/j.jmb.2013.12.024
    Abstract
    Conformational entropy is an important component of protein-protein interactions; however, there is no reliable method for computing this parameter. We have developed a statistical measure of residual backbone entropy in folded proteins by using the varphi-psi distributions of the 20 amino acids in common secondary structures. The backbone entropy patterns of amino acids within helix, sheet or coil form clusters that recapitulate the branching and hydrogen bonding properties of the side chains in the secondary structure type. The same types of residues in coil and sheet have identical backbone entropies, while helix residues have much smaller conformational entropies. We estimated the backbone entropy change for immunoglobulin complementarity-determining regions (CDRs) from the crystal structures of 34 low-affinity T-cell receptors and 40 high-affinity Fabs as a result of the formation of protein complexes. Surprisingly, we discovered that the computed backbone entropy loss of only the CDR3, but not all CDRs, correlated significantly with the kinetic and affinity constants of the 74 selected complexes. Consequently, we propose a simple algorithm to introduce proline mutations that restrict the conformational flexibility of CDRs and enhance the kinetics and affinity of immunoglobulin interactions. Combining the proline mutations with rationally designed mutants from a previous study led to 2400-fold increase in the affinity of the A6 T-cell receptor for Tax-HLAA2. However, this mutational scheme failed to induce significant binding changes in the already-high-affinity C225-Fab/huEGFR interface. Our results will serve as a roadmap to formulate more effective target functions to design immune complexes with improved biological functions.
    Source
    J Mol Biol. 2014 Apr 3;426(7):1583-99. doi: 10.1016/j.jmb.2013.12.024. Epub 2013 Dec 28.Link to article on publisher's site
    DOI
    10.1016/j.jmb.2013.12.024
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/25918
    PubMed ID
    24380763
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jmb.2013.12.024
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