Force Field Comparison through Computational Analysis of Capsular Polysaccharides of Streptococcus Pneumoniae Serotypes 19A and F

摘要

Modern Molecular Dynamics force fields, such as the CHARMM36 and GLYCAM06 carbohydrate force fields, are parametrised to reproduce behaviours for specific molecules under specific conditions in order to be able to predict the behaviour of similar molecular systems, where there is often no experimental data. Coupled with the sheer numberavailable, this makes choosing the appropriate force field a formidable task. For this reason it is important that modern force fields be regularly compared.Streptococcus pneumoniae is a cause of invasive pneumococcal disease (IPD) such as pneumonia and meningitis in children under five. While there are over 90 pneumococcal serotypes only a handful of these are responsible for disease. Immunisation with the conjugate vaccine PCV7, has markedly decreased invasive pneumoccocal disease. Following PCV7 immunisation, incidences of non-vaccine serotypes, especially serotype 19A, have increased. Serotype 19F's capsular polysaccharide differs from 19A's at a single linkage position. Where 19A possesses an a-D-Glcp-(1->3)-a-L-Rhap (G13R), 19F possesses an a-D-Glcp-(1->2)-a-L-Rhap (G12R) linkage. For this reason it was thought that a 19F conjugate would cross protect against 19A. Unfortunately PCV7 vaccination appears to have been largely ineffective against 19A disease.The lack of conformational information for the G12R and G13R disaccharides provided a good opportunity to compare the CHARMM and GLYCAM force fields. The dynamics of the G12R and G13R disaccharides were investigated under both CHARMM and GLYCAM.While we did identify some discrepancies, overall the force fields were in agreement inpredicting a more flexible G12R than the more restricted G13R. While it is possible that these differences account for the lack of 19F to 19A cross protectionprotection, further research is required.