Structural and Thermodynamic Approach to Peptide Immunogenicity
Structural and Thermodynamic Approach to Peptide Immunogenicity
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DOI：
10.1371/journal.pcbi.1000231
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发表时间：
2008-11-01
影响因子：
4.3
通讯作者：
Ascherman, Dana P.
中科院分区：
文献类型：
--
作者：
Camacho, Carlos J.;Katsumata, Yasuhiro;Ascherman, Dana P.
在体液免疫的常规范例中，B细胞识别其天然形式的同源抗原靶标。然而，众所周知，仅与天然蛋白质具有部分结构相似性的相对不稳定的肽可以触发识别天然蛋白质中发现的高级结构的抗体。在良好的热力学原理的基础上，这项工作揭示了免疫原性蛋白样基序的稳定性是合理化不同的线性肽表位诱导的不同体液免疫应答的关键参数。在这个范例中，具有最小量的稳定性的肽在蛋白样基序（X）周围的Δ G（X）< 0 kcal/mol）能够诱导对肽和天然蛋白具有相似亲和力的抗体，更弱稳定的肽（Δ G（X）> 0 kcal/mol）触发识别完整蛋白质但不识别肽的抗体，而不稳定的肽（Δ G（X）> 8 kcal/mol）不能产生针对肽或蛋白质的抗体。涉及来自自身抗原组氨酰-tRNA合成酶的肽的免疫实验验证了通过分子动力学模拟预测的具有不同相对稳定性的所选肽诱导与该理论一致的抗体应答。总的来说，这些研究提供了与免疫原性的结构基础相关的见解，同时，验证了这种形式的热力学和分子建模作为探测体液免疫应答的发展/进化的方法。
In the conventional paradigm of humoral immunity, B cells recognize their cognate antigen target in its native form. However, it is well known that relatively unstable peptides bearing only partial structural resemblance to the native protein can trigger antibodies recognizing higher-order structures found in the native protein. On the basis of sound thermodynamic principles, this work reveals that stability of immunogenic proteinlike motifs is a critical parameter rationalizing the diverse humoral immune responses induced by different linear peptide epitopes. In this paradigm, peptides with a minimal amount of stability (Delta G(X) < 0 kcal/mol) around a proteinlike motif (X) are capable of inducing antibodies with similar affinity for both peptide and native protein, more weakly stable peptides (Delta G(X) > 0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (Delta G(X) > 8 kcal/mol) fail to generate antibodies against either peptide or protein. Immunization experiments involving peptides derived from the autoantigen histidyl-tRNA synthetase verify that selected peptides with varying relative stabilities predicted by molecular dynamics simulations induce antibody responses consistent with this theory. Collectively, these studies provide insight pertinent to the structural basis of immunogenicity and, at the same time, validate this form of thermodynamic and molecular modeling as an approach to probe the development/evolution of humoral immune responses.