Laffy Julie M J, Dodev Tihomir, Macpherson Jamie A, Townsend Catherine, Lu Hui Chun, Dunn-Walters Deborah, Fraternali Franca
Randall Division of Cell and Molecular Biophysics, King's College London, UK.
Department of Immunobiology, King's College London, UK.
Prog Biophys Mol Biol. 2017 Sep;128:47-56. doi: 10.1016/j.pbiomolbio.2016.09.002. Epub 2016 Sep 14.
Human B cells produce antibodies, which bind to their cognate antigen based on distinct molecular properties of the antibody CDR loop. We have analysed a set of 10 antibodies showing a clear difference in their binding properties to a panel of antigens, resulting in two subsets of antibodies with a distinct binding phenotype. We call the observed binding multiplicity 'promiscuous' and selected physico-chemical CDRH3 characteristics and conformational preferences may characterise these promiscuous antibodies. To classify CDRH3 physico-chemical properties playing a role in their binding properties, we used statistical analyses of the sequences annotated by Kidera factors. To characterise structure-function requirements for antigen binding multiplicity we employed Molecular Modelling and Monte Carlo based coarse-grained simulations. The ability to predict the molecular causes of promiscuous, multi-binding behaviour would greatly improve the efficiency of the therapeutic antibody discovery process.
人类B细胞产生抗体，这些抗体基于抗体互补决定区（CDR）环的独特分子特性与其同源抗原结合。我们分析了一组10种抗体，它们对一组抗原的结合特性存在明显差异，从而产生了具有不同结合表型的两个抗体亚群。我们将观察到的结合多样性称为“多特异性”，选定的物理化学互补决定区3（CDRH3）特征和构象偏好可能是这些多特异性抗体的特征。为了分类在其结合特性中起作用的CDRH3物理化学性质，我们使用了由木寺因子注释的序列的统计分析。为了表征抗原结合多样性的结构-功能要求，我们采用了分子建模和基于蒙特卡洛的粗粒度模拟。预测多特异性、多结合行为的分子原因的能力将大大提高治疗性抗体发现过程的效率。
