Solvent Effect on the Anomeric Equilibrium in D-Glucose: A Free Energy Simulation Analysis

Sookhee Ha, Jiali Gao, Bruce Tidor, John W. Brady, Martin Karplus

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Abstract

The equilibrium between the α and β anomers of D-glucopyranose in aqueous solution has been investigated by free energy simulations that permit a separation of the intramolecular and intermolecular contributions to the free energy difference. The simulations correctly predict that the free energy difference between the two forms in aqueous solution is small; the calculated free energy difference, ΔG(β → α), is −0.31 ± 0.43 kcal/mol, in comparison with the experimental value of 0.33 kcal/mol. The calculated free energy difference is the result of near cancelation of two larger, statistically significant contributions, i.e., an intramolecular electrostatic term favoring the α anomer and an intermolecular solute-solvent interaction term favoring the β anomer. This result supports the conjecture that solvation stabilizes the β anomrr in water. There is a large difference in the intramolecular contribution to the anomeric equilibrium calculated in solution from the free energy simulation and the gas-phase minimum; this suggests that conformational averaging, modulated by the solvent, is significant even for the internal terms. An examination of the rotamer distribution in the hydroxymethyl side chain shows that the trans, gauche conformer is strongly disfavored in aqueous solution, in accord with experiment.

Original languageEnglish (US)
Pages (from-to)1553-1557
Number of pages5
JournalJournal of the American Chemical Society
Volume113
Issue number5
DOIs
StatePublished - 1991

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