4320880

Investigation of glycosidic linkages in O-antigen repeating units from Shigella and Salmonella pathogens: an NMR and MD simulation study using the additive and Drude polarizable force fields

Date
August 18, 2025

The O-antigen moiety of lipopolysaccharide is important for the function and virulence of many bacteria and has been recognized as a key target for protective immunity against several pathogens. In this study, model oligosaccharides were used to investigate the conformations of glycosidic linkages from structural entities present in the O-antigen repeating units of the well-known pathogens Shigella and Salmonella via a combination of experimental and computational techniques. Model compounds with intramolecular tethering and/or functional group modifications include chlorines that have been reported as high affinity oligosaccharide-based ligands were also included. Ranging from di- to tetrasaccharides, the compounds were subjected to one-microsecond molecular dynamics (MD) simulations with both the CHARMM36 Additive and Drude Polarizable state-of-the-art force fields. The intramolecular tether parameters were developed as part of the present study. In addition to yielding insights into the linkage conformational properties, the results allowed for validation of the force fields for sugars having the l absolute configuration present in most of the compounds. Analysis of the MD simulations included dihedral angle distributions of φ and ψ, potentials of mean force obtained from φ – ψ rotamer distributions, effective distances and ring puckering measurements allowing elucidation of structural information with the guidance of NMR chemical shift perturbation data. Three-bond spin–spin NMR coupling constants (3J) related to φ and ψ dihedral angles were calculated with Karplus-type relationships and showed notable agreement with 3J obtained from 1DLR, J-HMBC and IPAP selHSQMBC NMR experiments. The present structural insights of the studied oligosaccharides give a good understanding of the range of conformations adopted in the O-antigens and how tethering affects conformational properties of glycan macrocycles.

Co-Authors


Related Products

Thumbnail for Thermodynamic stabilization of conformations in Lewis antigens
Thermodynamic stabilization of conformations in Lewis antigens
Professor Frasier-Reid's carbohydrate research was characterized by insights into reaction mechanisms and conformational analysis…
Thumbnail for Optimizing the Drude polarizable force field for intrinsically disordered peptides and small proteins: balancing folded and unfolded states
Optimizing the Drude polarizable force field for intrinsically disordered peptides and small proteins: balancing folded and unfolded states
This study focuses on optimizing the Drude polarizable protein force field (FF) to enhance its ability to accurately describe the equilibrium between folded and unfolded states in intrinsically disordered peptides (IDPs) and small proteins, while preserving its reliability for globular and transmem…
Thumbnail for Optimization of the drude polarizable force Field (FF) targeting r(GACC) single-stranded tetranucleotide experimental data
Optimization of the drude polarizable force Field (FF) targeting r(GACC) single-stranded tetranucleotide experimental data
The Drude polarizable force field (Drude FF) for nucleic acids provides a promising framework for accurately modeling biomolecules in molecular dynamics simulations by explicitly incorporating atomic polarizability…
Thumbnail for ML-assisted optimization of the polarizable Drude general force field (DGenFF)
ML-assisted optimization of the polarizable Drude general force field (DGenFF)
Accurate predictions of microscopic structural and macroscopic experimental properties using MD simulations relies on the accuracy of the underlying force field (FF)…