Cryptococcus neoformans Capsular GXM Conformation and Epitope Presentation: A Molecular Modelling Study.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Michelle M KuttelStefan Oscarson

Abstract

The pathogenic encapsulated Cryptococcus neoformans fungus causes serious disease in immunosuppressed hosts. The capsule, a key virulence factor, consists primarily of the glucuronoxylomannan polysaccharide (GXM) that varies in composition according to serotype. While GXM is a potential vaccine target, vaccine development has been confounded by the existence of epitopes that elicit non-protective antibodies. Although there is evidence for protective antibodies binding conformational epitopes, the secondary structure of GXM remains an unsolved problem. Here an array of molecular dynamics simulations reveal that the GXM mannan backbone is consistently extended and relatively inflexible in both C. neoformans serotypes A and D. Backbone substitution does not alter the secondary structure, but rather adds structural motifs: β DGlcA and β DXyl side chains decorate the mannan backbone in two hydrophillic fringes, with mannose-6-O-acetylation forming a hydrophobic ridge between them. This work provides mechanistic rationales for clinical observations-the importance of O-acetylation for antibody binding; the lack of binding of protective antibodies to short GXM fragments; the existence of epitopes that elicit non-protective antibodies; ...Continue Reading

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Citations

Jan 31, 2021·Proceedings of the National Academy of Sciences of the United States of America·Conor J CrawfordStefan Oscarson

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Methods Mentioned

BETA
optical tweezers
acetylation

Software Mentioned

NAMD
house
VMD
psfgen
CHARMM36
CarbBuilder
CHARMM
Tcl

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