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首页> 外文期刊>Journal of Molecular Biology >Backbone flexibility of CDR3 and immune recognition of antigens.
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Backbone flexibility of CDR3 and immune recognition of antigens.

机译：CDR3的骨干灵活性和抗原的免疫识别。

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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 ?-ψ 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.
机译：构象熵是蛋白质与蛋白质相互作用的重要组成部分。但是，没有可靠的方法来计算此参数。通过使用常见二级结构中20个氨基酸的β-ψ分布，我们已经开发出一种统计方法来测量折叠蛋白中残留骨架的熵。螺旋，片状或卷曲状结构中氨基酸的主链熵模式形成簇，概括了二级结构类型侧链的支化和氢键键合性质。卷材和片材中相同类型的残基具有相同的主链熵，而螺旋残基具有更小的构象熵。我们从34个低亲和力T细胞受体和40个高亲和力Fabs的晶体结构的蛋白质结构的形成估计了免疫球蛋白互补决定区（CDRs）的骨架熵变化。令人惊讶地，我们发现，仅CDR3而非所有CDR的计算出的骨架熵损失与74种选择的复合物的动力学和亲和常数显着相关。因此，我们提出了一种简单的算法来引入脯氨酸突变，从而限制CDR的构象灵活性并增强免疫球蛋白相互作用的动力学和亲和力。结合脯氨酸突变与先前研究的合理设计的突变体，导致A6 T细胞受体对Tax-HLAA2的亲和力提高了2400倍。然而，该突变方案未能在已经高度亲和的C225-Fab / huEGFR界面中诱导显着的结合变化。我们的结果将作为路线图，以制定更有效的目标功能来设计具有改善的生物学功能的免疫复合物。

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