Conformational Dynamics of a Central Trisaccharide Fragment of the Le^aLe^x Tumor Associated Antigen Studied by NMR Spectroscopy and Molecular Dynamics Simulations

Abstract

Abstract Certain carbohydrate structures are recognized as cancer antigens, and identification of these and relevant epitopes are essential in fighting the disease. The trisaccharide β‐ D ‐Glc p NAc‐(1→3)‐β‐ D ‐Gal p ‐(1→4)‐β‐ D ‐Glc p NAc‐OMe represents a model for the central region of the Le a Le x hexasaccharide and it has herein been investigated by 1D 1 H, 1 H‐NOESY experiments to obtain effective interresidue proton–proton distances as well as by 2D J‐HMBC experiments to determine transglycosidic 3 J CH coupling constants. Molecular dynamics (MD) simulations using explicit water as solvent and three different carbohydrate force fields, namely, GLYCAM06, PARM22/SU01, and CHARMM2011, were employed for the interpretation of experimental data. Overall, the force field based MD simulations are able to reproduce the experimental data and the ψ torsion angle at the β‐(1→3)‐linkage is concluded to be flexible. In addition, different minor states were present for the three force fields with either anti‐ ψ or non‐ exo ‐anomeric conformations. Transitions between the exo ‐anomeric and the non‐ exo ‐anomeric conformations for the φ torsion angle at the β‐(1→4)‐linkage in one of the MD simulations were analyzed in detail. It was found that hydrogen‐bonding water molecules, interresidue hydrogen bonds and the transitions between antiperiplanar and synperiplanar conformations for the τ H torsion angle of an N‐acetyl group were all essential in the description of the glycosidic transition process. In particular, the transition of τ H may be a general way of regulating other transitions into less populated but biologically important conformational regions.