Kadirvelraj Renuka, Gonzalez-Outeiriño Jorge, Foley B Lachele, Beckham Meredith L, Jennings Harold J, Foote Simon, Ford Michael G, Woods Robert J
Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8149-54. doi: 10.1073/pnas.0602815103. Epub 2006 May 16.
Bacterial surface capsular polysaccharides (CPS) that are similar in carbohydrate sequence may differ markedly in immunogenicity and antigenicity. The structural origin of these phenomena is poorly understood. Such a case is presented by the Gram-positive bacteria Streptococcus agalactiae (Group B Streptococcus; GBS) type III (GBSIII) and Streptococcus pneumoniae (Pn) type 14 (Pn14), which share closely related CPS sequences. Nevertheless, antibodies (Abs) against GBSIII rarely cross-react with the CPS from Pn14. To establish the origin for the variation in CPS antigenicity, models for the immune complexes of CPS fragments from GBSIII and Pn14, with the variable fragment (Fv) of a GBS-specific mAb (mAb 1B1), are presented. The complexes are generated through a combination of comparative Ab modeling and automated ligand docking, followed by explicitly solvated 10-ns molecular dynamics simulations. The relationship between carbohydrate sequence and antigenicity is further quantified through the computation of interaction energies using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method, augmented by conformational entropy estimates. Despite the electrostatic differences between Pn14 and GBSIII CPS, analysis indicates that entropic penalties are primarily responsible for the loss of affinity of the highly flexible Pn14 CPS for mAb 1B1. The similarity of the solution conformation of the relatively rigid GBSIII CPS with that in the immune complex characterizes the previously undescribed 3D structure of the conformational epitope. The analysis provides a comprehensive interpretation for a large body of biochemical and immunological data related to Ab recognition of bacterial polysaccharides and should be applicable to other Ab-carbohydrate interactions.
碳水化合物序列相似的细菌表面荚膜多糖（CPS）在免疫原性和抗原性上可能存在显著差异。这些现象的结构起源尚不清楚。革兰氏阳性菌无乳链球菌（B组链球菌；GBS）III型（GBSIII）和肺炎链球菌（Pn）14型（Pn14）就是这样的例子，它们具有密切相关的CPS序列。然而，针对GBSIII的抗体（Ab）很少与Pn14的CPS发生交叉反应。为了确定CPS抗原性变异的起源，本文展示了GBSIII和Pn14的CPS片段与GBS特异性单克隆抗体（mAb 1B1）的可变片段（Fv）形成的免疫复合物模型。这些复合物是通过比较抗体建模和自动配体对接相结合生成的，随后进行了明确溶剂化的10纳秒分子动力学模拟。通过使用分子力学-广义玻恩表面积（MM-GBSA）方法计算相互作用能，并结合构象熵估计，进一步量化了碳水化合物序列与抗原性之间的关系。尽管Pn14和GBSIII CPS之间存在静电差异，但分析表明，熵惩罚主要导致高度灵活的Pn14 CPS对mAb 1B1亲和力的丧失。相对刚性的GBSIII CPS的溶液构象与免疫复合物中的构象相似，这表征了构象表位此前未被描述的三维结构。该分析为与抗体识别细菌多糖相关的大量生化和免疫数据提供了全面的解释，并且应该适用于其他抗体-碳水化合物相互作用。
