Kato K, Watanabe T, Yamaguchi T

Chemical and Pharmaceutical Bulletin, 73 (2025)

Glycans, as one of the fundamental biomolecules alongside nucleic acids and proteins, play critical roles in biological processes, including glycoprotein folding, transport, degradation, and cell–cell interactions. Despite their biological importance, the structural analysis of glycans remains challenging due to their high flexibility and complex branched structures. This study addresses these challenges by combining molecular dynamics (MD) simulations and NMR spectroscopy to obtain dynamic conformational ensembles of glycans. Nonlinear correlation analyses, specifically Hilbert–Schmidt independence criterion and maximal information coefficient, were applied to decipher the structural dynamics of glycans. The study focused on GM3 trisaccharides and high-mannose glycans (GM9, M9, and M8B), uncovering the roles of glycosidic dihedral angles and intramolecular hydrogen bonds in stabilizing specific conformations. Key correlations between glycosidic linkages and hydrogen bonds were identified, offering insights into the conformational changes that underpin glycan bioactivity. Notably, the removal of specific mannose residues disrupts hydrogen bond networks, expanding conformational space and influencing glycoprotein fate in the endoplasmic reticulum. By integrating MD simulations, NMR validation, and nonlinear multivariate analysis, this study provides a robust framework for understanding glycan structural dynamics. These findings have broad implications for glycoengineering, glycan-based drug discovery, and the design of therapeutics targeting structurally dynamic biomolecules, such as intrinsically disordered proteins.