Abstract:
:The mechanism by which antibodies elicited against protein-derived peptides achieve cross-reactivity with their cognate proteins remains unknown. To address this question, we have carried out the complete thermodynamic characterization of the association of a monoclonal antibody (260.33.12) raised against a peptide (SNpep) derived from staphylococcal nuclease (SNase) with both eliciting peptide and cognate protein. Although both ligands bind with similar affinity (Kd=0.42 μM and 0.30 μM for protein and peptide, respectively), protein and peptide binding have highly different thermodynamic signatures: peptide binding is characterized by a large enthalpic contribution (ΔH=-7.7 kcal/mol) whereas protein binding is dominated by a large entropic contribution (-TΔS=-7.2 kcal/mol). The structure of the SNpep:Fab complex, determined by X-ray diffraction, reveals that the bound conformation of the peptide differs from the conformation of the corresponding loop region in crystal structures of free SNase. The energy difference, estimated by molecular dynamics simulations between native SNase and a model in which the Ω-loop is built in the conformation of the Fab-bound peptide, shows that the energetic cost of adopting this conformation is compatible with the enthalpic cost of binding the protein vis-à-vis the peptide. These results are compatible with a mechanism by which the anti-peptide antibody recognizes the cognate protein: high affinity is maintained upon binding a non-native conformation by offsetting enthalpic penalties with reduced entropic losses. These findings provide potentially useful guidelines for the identification of linear epitopes within protein sequences that are well suited for the development of synthetic peptide vaccines.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Armstrong A,Hildreth JEK,Amzel LMdoi
10.1016/j.jmb.2013.02.031subject
Has Abstractpub_date
2013-06-12 00:00:00pages
2027-2038issue
11eissn
0022-2836issn
1089-8638pii
S0022-2836(13)00146-0journal_volume
425pub_type
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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journal_title:Journal of molecular biology
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