Molecular interaction between typhoid toxin and n-linked glycans: an in-silico investigation

Abstract

Typhoid fever is an enteric fever along with the systemic illness of abdominal pain and fever. The primary causative organism responsible for typhoid fever is Salmonella enterica serovar Typhi (S. Typhi) bacteria. Typhoid toxin (A2B5 configuration) is found to be the key player responsible for developing the clinical symptoms during the Salmonella Typhi human infection. The B subunit is the homopentamer having PltB monomer, which plays the central role during the entry of the toxin into the host cells. Recent experimental studies suggest that each PltB monomer has three glycan-binding sites. These site mainly prefers to bind with multiantennary N-linked glycans with a varying degree of affinity among three binding sites. These interactions are mainly governed by the terminal sialic acid residues which can be modifed also. Herein, we studied the conformational dynamics and the binding mechanisms of five different N-glycan motifs (combination of modified and unmodified) through all atom molecular dynamics (MD). The conformational variability of the tri-saccharide motif was estimated through analysising the dihedral space of torsional angles as well as the puckering conformations. For elucidating the recognition mechanism, we employed the molecular mechanism generalized Born surface area (MM/GBSA) method. In terms of binding free energy, modifed glycans show better affinity compared to the unmodified carbohydrates. In the case of modified glycans, hydrogen bonding occurs via the Neu5Ac and acetyl modification of the glycans. In contrast, in the case of unmodified glycans, the binding occurs via the Neu5Ac, Gal and GlcNAc. Overall, our study may help to understand the interaction mechanisms of the attachement of typhoid toxin to the cell surface and to design glycomimetic molecules to prevent the disease.