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dc.contributor.authorAustin, Berinyuy Yongye
dc.description.abstractNeisseria meningitidis (N. meningitidis) is the leading cause of bacterial meningitis in neonates. The capsule comprises of polysaccharides that serve as key virulence factors that mask vulnerable epitopes and impart antiphagocytic properties. Thirteen strains are known, based on antibody recognition of the capsular polysaccharides (CPS). Only five strains: A, B, C, W-135 and Y are responsible for meningococcal disease. Currently, CPS-conjugate vaccines are available only against types A, C, W-135 and Y. Type B is weakly immunogenic because its CPS, alpha.-(2,8)-linked polysialic acid, is a self-antigen present in the gangliosides of human neural cell-adhesion molecules. Attempts to boost the immunogenicity of CPSs from type B have involved chemical modifications, with the primary goal being the induction of cross-reactivities between antibodies raised against the modified CPS with the bacterial CPS. Herein, computational protocols are employed to elucidate the conformational properties of haptens from the CPS of N. meningitidis B, and to probe the effects of chemical group modifications on their conformational properties. A generalizable biomolecular force field, GLYCAM06, aimed at modeling neutral and charged carbohydrates, such as the N. meningitidis CPSs, has been developed. The force field is tested on its ability to reproduce the experimental and QM vibrational frequencies of carbohydrates, experimental rotational energy barriers and quantum mechanics (QM) rotational energy curves of small molecules. Solution phase tests determine whether explicit-solvent molecular dynamics (MD) simulations, employing 3GLYCAM06, can reproduce experimental NMR observables such homonuclear scalar J-coupling constants, nuclear Overhauser enhancement distances and the populations of rotational isomeric states. Explicit-solvent thermodynamic integration MD simulations are employed to determine whether GLYCAM06 can be utilized to predict the binding modes of carbohydrate-protein interactions. The experimental relative affinities of a monoclonal antibody for a series of trisaccharides from the capsule of Shigella flexneri variant Y are employed as benchmarks. For structural properties, a pentasaccharide is docked to crystal structures and to a comparative model of the antibody. The docking simulations underscore the importance of employing high quality protein structures in generating theoretical models of protein-carbohydrate complexes. Refining the theoretical complexes via explicit-solvent MD simulations, significantly improves quality in terms of reproducing experimental hydrogen bonds.
dc.subjectNeisseria meningitidis
dc.subjectconformational properties
dc.subjectThermodynamic integration
dc.subjectcomparative modeling
dc.subjectmolecular dynamics simulations
dc.subjectensemble-average charges
dc.subjectforce field development
dc.subjectcarbohydrate-protein interactions
dc.titleComputational elucidation of the structural basis for the antigenicity of bacterial capsular polysaccharides
dc.title.alternativeNeisseria meningitidis
dc.description.advisorRobert J. Woods
dc.description.committeeRobert J. Woods
dc.description.committeeLionel A. Carreira
dc.description.committeeKelley W. Moremen
dc.description.committeeRobert A. Scott

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