Iduronate Ring Puckering Effects on Preferred Glycosidic Linkage Conformations in Heparin/Heparan Sulfate and...

The conformation of a glycosaminoglycan (GAG) carbohydrate biopolymer is dependent upon the ring puckering states of its constituent monosaccharide residues and the dihedral angles (φ, ψ) of the glycosidic linkages connecting these residues. In the context of GAGs, the monosaccharide residue iduronate (IdoA; the conjugate base of iduronic acid) is able to take on both chair and boat-like ring pucker states. All-atom explicit-solvent molecular dynamics simulations were applied to determine the extent to which IdoA ring pucker state affects the conformational preferences of (φ, ψ) in 16 different IdoA-containing disaccharides derived from the GAGs heparin/heparan sulfate and dermatan sulfate. Using the extended-system adaptive biasing force (eABF) method, the complete free-energy surface ΔG(φ, ψ) was computed for each disaccharide with its IdoA ring restrained separately to the ¹C₄, ²S_O, B_3,O, or ⁴C₁ ring pucker state. Global-minimum ΔG(φ, ψ) values resided within broad ΔG(φ, ψ) basins, and both ring pucker state and sulfation status influenced basin shape and size. Various sulfoforms of the disaccharide IdoAα1-4GlcNS had prominent secondary-minimum basins distinct from the global-minimum basins, and these secondary-minimum basins may manifest as metastable states in standard (nonbiased) molecular dynamics simulations on the 1-microsecond timescale. As such, the present results provide a reference for assessing (φ, ψ) sampling in nonbiased molecular dynamics simulations of GAGs and demonstrate the interplay between IdoA ring puckering, glycosidic linkage dihedral rotation, and sulfation status in contributing to GAG conformational preferences.