Investigating Conformational Dynamics of Lewis Y Oligosaccharides and Elucidating Blood Group Dependency of Cholera Using Molecular Dynamics

Rajarshi Roy; Biplab Ghosh; Parimal Kar

doi:10.1021/acsomega.9b03398

Investigating Conformational Dynamics of Lewis Y Oligosaccharides and Elucidating Blood Group Dependency of Cholera Using Molecular Dynamics

ACS Omega. 2020 Feb 19;5(8):3932-3942. doi: 10.1021/acsomega.9b03398. eCollection 2020 Mar 3.

Authors

Rajarshi Roy¹, Biplab Ghosh², Parimal Kar¹

Affiliations

¹ Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore 453552, India.
² High Pressure and Synchrotron Radiation Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.

Abstract

Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. 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. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, ⁴C₁ and ¹C₄ puckers were sampled for all but GalNAc monosaccharides, while either the ⁴C₁ (GlcNAc, Gal, GalNAc) or ¹C₄ (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the ⁴C₁ to ¹C₄ pucker was sampled for GlcNAc and Gal in both oligosaccharides. 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. Both oligosaccharides adopted an open conformation in the CT binding site. 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. 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. 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. 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. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.