Dependence of Pyranose Ring Puckering on Anomeric Configuration: Methyl Idopyranosides

Abstract

In the aldohexopyranose idose, the unique presence of three axial ring hydroxyl groups causes considerable conformational flexibility, rendering it challenging to study experimentally and an excellent model for rationalising the relationship between puckering and anomeric configuration. Puckering in methyl α- and β-l-idopyranosides was predicted from kinetically rigorous 10 μs simulations using GLYCAM11 and three explicit water models (TIP3P, TIP4P and TIP4P-EW). In each case, computed pyranose ring three-bond (vicinal) 1H-1H spin-couplings (3JH,H) trended with NMR measurements. These values, calculated puckering exchange rates and free energies were independent of the water model. The α- and β-anomers were 1C4 chairs for 85% and >99% of their respective trajectories and underwent 1C4→4C1 exchange at rates of 20 μs-1 and 1 μs-1. Computed α-anomer 1C4↔4C1 puckering rates depended on the exocyclic C6 substituent, comparing hydroxymethyl with carboxyl from previous work. The slower kinetics and restricted pseudorotational profile of the β-anomer were caused by water occupying a cavity bounded by the anomeric 1-O-methyl and the C6 hydroxymethyl groups. This finding rationalises the different methyl α- and β-l-idopyranoside 3JH,H values. Identifying a relationship between idopyranose anomeric configuration, μs-puckering and water structure facilitates engineering of biologically and commercially important derivatives and underpins deciphering presently elusive structure-function relationships in the glycome.

Revision of the GROMOS 56A6CARBO force field: Improving the description of ring‐conformational equilibria in hexopyranose‐based carbohydrates chains

“…Compared to the experimental results of Ref. for α‐ and β‐Ido (−3.4 and 2.7 kJ mol −1 , respectively), a positive shift is indeed observed for the α‐anomer and a negative one for the β‐anomer, albeit of a smaller magnitude than suggested by 56A6 CARBO_R . The ΔF i values calculated using the force field are 7.5 and 4.5 kJ mol −1 , respectively, which means, in particular, that although 56A6 CARBO_R correctly predicts a dominant 1 C 4 chair for α‐Ido, it is apparently at odd with experiment in predicting a dominant 4 C 1 chair for α‐Me‐Ido.…”

“…To our knowledge, the only experimental results available for the ring‐conformational equilibrium of an O 1 ‐methyl‐hexopyranoside concern α‐Me‐Ido and β‐Me‐Ido, where population ratios inferred from NMR J ‐coupling constants ( 4 C 1 : 1 C 4 ratios of 35:65 and 76:24, respectively, see Supporting Information of the indicated reference, Table S8; the ratios provided for the l ‐compound in the two‐site rigid model have been inverted here to be representative for the d ‐compound) suggest chair‐inversion free energies of −1.1 and 2.6 kJ mol −1 , respectively. Compared to the experimental results of Ref.…”

“…To our knowledge, the only experimental results available for a O 1 ‐methylated hexopyranose concern Ido, and suggest ΔF i of −1.1 and 2.6 kJ mol −1 , respectively, for the α‐ and β‐anomers (see Supporting Information of Ref. , Table S8 therein; the ratios provided for the l ‐compound in the two‐site rigid model must be inverted to be representative for the d ‐compound).…”

Fluoro‐Carba‐Sugars are Glycomimetic Activators of the glmS Ribozyme

“…This flexibility leads to observed vicinal coupling constants that are averaged over the constants of the corresponding conformers. Thus, the coupling constants of 14 and 2 are significantly higher than the calculated values for methyl β‐ l ‐idopyranoside ( 3 J H3‐H4 = 3 J H3‐H2 =3.0 Hz) in the favored 1 C 4 conformation . Similar conformational flexibility could already be demonstrated for the gem ‐difluorocarba‐sugar analog of methyl‐β‐ l ‐idopyranoside .…”

Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans

“…While the ring flip dynamics were not captured by this work, long timescale simulations of IdoA using GLYCAM have previously shown experimentally consistent ring populations. 53 The 3 J HH coupling analysis also suggested that the terminal GlcA ring may not exclusively adopt the expected 4 C 1 conformation.…”