Effects of Glucosylation and O-Acetylation on the Conformation of Shigella flexneri Serogroup 2 O-Antigen Vaccine Targets
- 23 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Physical Chemistry B
- Vol. 124 (14), 2806-2814
- https://doi.org/10.1021/acs.jpcb.0c01595
Abstract
Shigellosis is an enteric disease with high morbidity and mortality, particularly in developing countries. There is currently no licensed vaccine available. Most infection is caused by Shigella flexneri, of which 30 serotypes have been recognized based on O-antigen polysaccharide structure. Almost all S. flexneri serotypes share the same repeating unit backbone (serotype Y), with varying glucosylation, O-acetylation and phosphorylation. The O-antigen is the primary vaccine target; the vaccine valency (and hence cost) can be reduced by cross-protection. Our planned systematic conformational study of S. flexneri starts here with 2a, the dominant cause of infection globally. We employ microsecond molecular dynamics simulations to compare the conformation of the unsubstituted serotype Y backbone with the serogroup 2 O-antigens, to investigate the effect of glucosylation and O-acetylation (O-factor 9) on conformation. We find that serotype Y is highly flexible, whereas glucosylation in 2a restricts flexibility and induces C-curve conformations. Further, the glucose side-chains adopt two distinct conformations, corroborated by the antibody-bound crystal structure data. Additional substitution on O-3 of rhamnose A (whether O-acetylation in 2a or glucosylation in 2b) induces helical conformations. Our results suggest that the O-3-acetylated 2a antigen will elicit cross-protection against 2b, as well as other serotypes containing O-factor 9.Funding Information
- University of Cape Town
- National Research Foundation (103805, 109643, 111704)
This publication has 53 references indexed in Scilit:
- Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000The Lancet, 2012
- Visualisation of cyclic and multi-branched molecules with VMDJournal of Molecular Graphics and Modelling, 2009
- Chapter 2 Quantifying Uncertainty and Sampling Quality in Biomolecular SimulationsAnnual Reports in Computational Chemistry, 2009
- CHARMM Additive All-Atom Force Field for Glycosidic Linkages between HexopyranosesJournal of Chemical Theory and Computation, 2009
- Overview of Glycoconjugate AnalysisCurrent Protocols in Protein Science, 2009
- Additive empirical force field for hexopyranose monosaccharidesJournal of Computational Chemistry, 2008
- O-Acetylation in the O-specific polysaccharide isolated from Shigella flexneri serotype 2aCarbohydrate Research, 2007
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983