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首页> 外文期刊>Journal of Molecular Biology >Structural and thermodynamic insights into the recognition of native proteins by anti-peptide antibodies
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Structural and thermodynamic insights into the recognition of native proteins by anti-peptide antibodies

机译：通过结构和热力学洞察抗肽抗体识别天然蛋白

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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.
机译：针对蛋白衍生肽引发的抗体与其同源蛋白发生交叉反应的机制仍然未知。为了解决这个问题，我们已经完成了针对源自葡萄球菌核酸酶（SNase）的肽（SNpep）产生的单克隆抗体（260.33.12）与引发肽和关联蛋白的关联的完整热力学表征。尽管两个配体都以相似的亲和力结合（蛋白质和肽的Kd分别为0.42μM和0.30μM），但是蛋白质和肽的结合具有非常不同的热力学特征：肽结合的特征是焓的贡献很大（ΔH=-7.7 kcal / mol ），而蛋白质结合则主要由大的熵贡献（-TΔS=-7.2 kcal / mol）决定。通过X射线衍射确定的SNpep：Fab复合物的结构表明，肽的结合构象与游离SNase晶体结构中相应环区的构象不同。通过天然SNase与通过Fab结合肽的构象构建Ω环的模型之间的分子动力学模拟估算的能量差表明，采用这种构象的能量成本与结合的焓成本兼容蛋白质相对于肽。这些结果与抗肽抗体识别同源蛋白质的机制相吻合：通过抵消焓损失减少的熵损失，在结合非天然构象时保持高亲和力。这些发现为鉴定适合开发合成肽疫苗的蛋白质序列中的线性表位提供了潜在有用的指导。

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