Cholera is caused by the pathogen Vibrio cholerae. More than 1.2 million cases were reported in 2017 all over the world, with a fatality rate of 0.5.

(1) Among all of these blood-group-dependent diseases, cholera is one of the deadliest and epidemic diseases in human history and most prevalent in the African subcontinent. There is a strict variation in the blood group type and frequencies among the human population throughout the world, which is a result of the genetic pressure giving protection from different infectious diseases. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. Moreover, we have investigated the molecular basis of recognition of Le Y oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme.

Both oligosaccharides adopted an open conformation in the CT binding site.

Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. In aMD, the complete transition from the 4C 1 to 1C 4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C 1 and 1C 4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C 1 (GlcNAc, Gal, GalNAc) or 1C 4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. The flexible nature of both oligosaccharides was displayed in aMD simulations. Herein, we studied the conformational dynamics of Lewis Y (Le Y) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo–blood group antigens at a secondary binding site. Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease.

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