Dependence of pyranose ring puckering on anomeric configuration: methyl idopyranosides.

In the aldohexopyranose idose, the unique presence of flexibility, rendering it challenging to study experimentally and an three axial ring hydroxyl groups causes considerable conformational excellent model for rationalizing the relationship between puckering and anomeric configuration. Puckering in methyl alpha- and beta-L-idopyranosides was predicted from kinetically rigorous 10 mu s simulations using GLYCAM11 and three explicit water models (TIP3P, TIP4P, and TIP4P-EW). In each case, computed pyranose ring three-bond (vicinal) H-1-H-1 spin couplings ((3)J(H,H)) trended with NMR measurements. These values, calculated puckering exchange rates and free energies, were independent of the water model. The alpha- and beta-anomers were C-1(4) chairs for 85 and >99% of their respective trajectories and underwent C-1(4)-> C-4(1) exchange at rates of 20 mu(-1) and 1 mu s(-1). Computed alpha-anomer C-1(4)<-> C-4(1) puckering rates depended on the exocyclic C6 substituent, comparing hydroxymethyl with carboxyl from previous work. The slower kinetics and restricted pseudorotational profile of the beta-anomer were caused by water occupying a cavity bounded by the anomeric 1-O-methyl and the C6 hydroxymethyl groups. This finding rationalizes the different methyl alpha- and beta-L-idopyranoside (3)J(H,H) values. Identifying a relationship between idopyranose anomeric configuration, microsecond puckering, and water structure facilitates engineering of biologically and commercially important derivatives and underpins deciphering presently elusive structure-function relationships in the glycome.