Abstract

The capsules of the Neisseria meningitidis bacteria contain carbohydrate polymers. These capsular polysaccharides (CPSs), mostly polyanionic, extend from cell walls around the organisms. Their strategic location at the surface makes them key determinants of virulence and invasiveness, and thus are targeted by the host's immune system. In the course of infection, the carbohydrate capsule protects the pathogen from antibody recognition and from phagocytosis. Serotypes have been identified based on the carbohydrate make up of the capsules. But only five (A, B, C, W-135 and Y) have historically caused invasive meningococcal diseases. To provide a rationale for the structural features that are responsible for mediating the specificity and antigenicity of their interactions with antibodies requires accurate representation of the three-dimensional structures and conformational behaviour of the CPS fragments.

We have developed a set of parameters in the carbohydrate force field, GLYCAM, for conformational analysis and prediction of the binding modes of the CPSs with their respective antibodies. The parameters were fit to quantum mechanical data generated at the B3LYP/6-31++G(2d, 2p)//HF/6-31G(d) as well as B3LYP/6-31++G(2d, 2p)//HF/6-31+G(d,p) levels of theory on small representative compounds. These new parameters reproduce experimental scalar J-couplings, NOEs, and rotamer populations, as shown by MD studies on haptens of N. meningitidis serotypes A and B. The parameters have also been used to predict the solution complexes of N. meningitidis strains B and C, with their specific antibody-binding fragments.

Strain B                                                                 Strain C

Strain A

Fig 1. The basic repeat units of the capsular polysaccharides from the three most virulent strains of N. meningitidis.