Comparative simulation of pneumococcal serogroup 19 polysaccharide repeating units with two carbohydrate force fields

Streptococcus pneumoniae causes meningitis, pneumonia and severe invasive disease (IPD) in young children. Although widespread infant immunisation with the PCV7 seven-valent pneumococcal conjugate vaccine has led to a dramatic decrease in IPD, infections due to non-vaccine serotypes, particularly serotype 19A, have increased. As the 19F polysaccharide differs from 19A at a single linkage position, it was assumed that PCV7 (containing 19F) would cross-protect against 19A disease. However, vaccination with PCV7 results in only 26% effectiveness against IPD caused by 19A. We explored the conformations and dynamics of the polysaccharide repeating units from serotypes 19F and 19A, comparing free energy surfaces for glycosidic linkages with 100ns aqueous molecular dynamics simulations of the di- and trisaccharide components. All calculations were performed with both the CHARMM and the GLYCAM carbohydrate force fields to establish whether the choice of model affects the predicted molecular behaviour. Although we identified key differences between the force fields, overall they were in agreement in predicting a 19F repeating unit with a wider range of conformation families than the more restricted 19A trisaccharide. This suggests a probable conformational difference between the 19F and 19A polysaccharides, which may explain the low cross-protection of 19F vaccines against 19A disease.