Structural elucidation of type III group B Streptococcus capsular polysaccharide using molecular dynamics simulations: the role of sialic acid

González-Outeiriño, Jorge; Kadirvelraj, Renuka; Woods, Robert J.

doi:10.1016/j.carres.2004.12.034

Cited by 49 publications

(54 citation statements)

References 29 publications

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“…The conformational entropy, associated with the change in the low-frequency, large-amplitude motions of the -angles, was predicted to be negligible for GBSIII, consistent with the observation that the free CPS rarely exhibits transitions in the backbone -angles (12). Thus, because the GBSIII CPS is relatively rigid in solution, and binds in essentially the solution conformation, there was no additional conformational entropic penalty upon its binding to the Fv, resulting in a favorable net binding energy of Ϫ4.9 kcal⅐mol Ϫ1 .…”

Section: Generation Of the Cps-fv Complexessupporting

confidence: 71%

“…The helical conformation of the GBSIII CPS in the model immune complex is comparable with that of the free CPS in solution (12), as evidenced by the relatively low rmsd of 4.3 Å between the nonhydrogen atoms of the bound and free CPS fragments (see Fig. 5, which is published as supporting information on the PNAS web site).…”

Section: Discussionmentioning

confidence: 89%

“…In the case of carbohydrates, it is particularly appropriate to focus on the conformational entropy associated with the interglycosidic torsion angles (32). Changes in the backbone -angles may be used to characterize the conformational differences between the GBSIII and Pn14 CPS (12); thus, these were exclusively selected for analysis.…”

Section: Methodsmentioning

confidence: 99%

“…On the basis of the contact analysis, it was concluded that only CPS repeat units IV and V interacted specifically with the CDRs, so the covariance analysis was limited to the -angles associated with these units, selected at 1-ps intervals from the 10-ns MD of the CPS-Fv complexes and the 50-ns MD of the free CPS (12). From the determinants of the covariance matrices for the torsion angles in the bound ( b ) and free states ( f ), the relative conformational entropies were derived by using Eq.…”

Section: Methodsmentioning

confidence: 99%

“…NMR spectroscopic and computational studies of the GBSIII CPS indicate that the PS adopts on average a helical conformation, in which the Neu5Ac residues are displayed on the surface of the helix, while the immunodominant sequence lines the helical core (11,12). The Neu5Ac residues play a major role in CPS antigenicity and GBS virulence, and it has been proposed (9) and recently confirmed (12) that these residues exert conformational control over the CPS.…”

Section: S Treptococcus Agalactiae [Group B Streptococcus (Gbs)] Andmentioning

confidence: 97%

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Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

Kadirvelraj

González-Outeiriño

Foley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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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. S treptococcus agalactiae [Group B Streptococcus (GBS)] andStreptococcus pneumoniae (Pn) are responsible for the majority of life-threatening cases of septicemia, meningitis, and pneumonia in neonates (1, 2). Gram-positive bacteria, such as GBS and Pn, are classified into serotypes according to the unique carbohydrate sequence of the bacterial surface capsular polysaccharide (CPS) and protein antigens. Serotypes vary in antigenicity, immunogenicity, virulence, and geographical distribution (3). Quantification of the structural and dynamic properties responsible for the affinity and specificity of antigenic oligosaccharide-antibody (Ab) interactions is a crucial step in furthering the understanding of the immune response to bacterial and fungal pathogens. In GBS, the CPS is a high-molecularweight polymer composed of varying sequences of ␤-D-, and sometimes L-rhamnopyranose. The glyceryl side chain of the Neu5Ac residues may also be Oacetylated (4). In all GBS strains identified to date, the Neu5Ac residues occur in the terminal position on the side-chain branches of the polymeric repeat unit of the CPS. They play an important role in defining the antigenicity and immunogenicity of the CPS (5). Variations within the CPS sequence result in the nine kno...

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Section: Generation Of the Cps-fv Complexessupporting

confidence: 71%

Section: Discussionmentioning

confidence: 89%