BACKGROUND Antibody, the primary effector molecule of the immune system, evolves after initial encounter with the antigen from a precursor form to a mature one to effectively deal with the antigen. Antibodies of a lineage diverge through antigen-directed isolated pathways of maturation to exhibit distinct recognition potential. In the context of evolution in immune recognition, diversity of antigen cannot be ignored. While there are reports on antibody lineage, structural perspective with respect to diverse recognition potential in a lineage has never been studied. Hence, it is crucial to evaluate how maturation leads to topological tailoring within a lineage enabling them to interact with significantly distinct antigens. RESULTS A data-driven approach was undertaken for the study. Global experimental mouse and human antibody-antigen complex structures from PDB were compiled into a coherent database of germline-linked antibodies bound with distinct antigens. Structural analysis of all lineages showed variations in CDRs of both H and L chains. Observations of conformational adaptation made from analysis of static structures were further evaluated by characterizing dynamics of interaction in two lineages, mouse VH1-84 and human VH5-51. Sequence and structure analysis of the lineages explained that somatic mutations altered the geometries of individual antibodies with common structural constraints in some CDRs. Additionally, conformational landscape obtained from molecular dynamics simulations revealed that incoming pathogen led to further conformational divergence in the paratope (as observed across datasets) even while maintaining similar overall backbone topology. MM-GB/SA analysis showed binding energies to be in physiological range. Results of the study are coherent with experimental observations. CONCLUSIONS The findings of this study highlight basic structural principles shaping the molecular evolution of a lineage for significantly diverse antigens. Antibodies of a lineage follow different developmental pathways while preserving the imprint of the germline. From the study, it can be generalized that structural diversification of the paratope is an outcome of natural selection of a conformation from an available ensemble, which is further optimized for antigen interaction. The study establishes that starting from a common lineage, antibodies can mature to recognize a wide range of antigens. This hypothesis can be further tested and validated experimentally.

中文翻译：

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解密抗体中免疫识别的进化。

背景技术抗体是免疫系统的主要效应分子，在与抗原初次接触后就从前体形式进化为成熟的形式，以有效地处理抗原。谱系的抗体通过抗原定向的成熟途径分离，从而展现出独特的识别潜力。在免疫识别进化的背景下，抗原的多样性不容忽视。尽管有关于抗体谱系的报道，但从未研究关于谱系中多种识别潜力的结构观点。因此，至关重要的是评估成熟度如何导致谱系内的拓扑剪裁，使其能够与明显不同的抗原相互作用。结果本研究采用了数据驱动的方法。将来自PDB的整体实验性小鼠和人抗体-抗原复合物结构编译为与不同抗原结合的种系相关抗体的连贯数据库。所有谱系的结构分析均显示H和L链的CDR均发生变化。通过表征小鼠VH1-84和人类VH5-51两种谱系的相互作用动力学，进一步评估了通过静态结构分析得出的构象适应性观察结果。谱系的序列和结构分析说明，体细胞突变改变了某些抗体中具有常见结构限制的单个抗体的几何形状。另外，从分子动力学模拟获得的构象构象表明，即使保持相似的总体主链拓扑结构，传入病原体也导致互补位进一步构象发散（如在数据集上观察到的）。MM-GB / SA分析显示结合能在生理范围内。研究结果与实验观察一致。结论这项研究的发现强调了基本的结构原理，这些原理影响了显着多样的抗原谱系的分子进化。谱系的抗体遵循不同的发育途径，同时保留种系的印迹。根据这项研究，可以得出结论，对位互补结构的多样化是从可用集合中自然选择构象的结果，进一步优化了抗原相互作用。该研究确定，从共同的血统开始，抗体可以成熟以识别多种抗原。该假设可以进一步测试和实验验证。