and experimental results confirm the equilibrium between the two chair conformers of idose in solution. 

After analyzing the role that some torsional interactions have in modulating the inverted chair free energy curves for both the α and β series of d- aldopyranoses, we tested a new set of parameters which proved to be quite successful in recovering the trend of the inverted chair free energy for all 16 stereoisomers under study. Our parametrization reproduces free energy differences in accordance to experimental and theoretical data always within 5 kJ/mol, but in most cases within 2.5 kJ/mol, that is, 1 k b T . A closer agreement with the theoretical model of Angyal 62 or Vijayalakshmi and coworkers 63 is probably not needed, given the uncertainties to which these models are subjected. Indeed, while the theoretical models do not provide any confidence interval, an approximate picture can be made by comparing the theoretical results with experimental data on idose $^{67}$, which roughly fall within a 2-3 kJ/mol interval. 

The improvement attained with the introduction of this new parameter set is to our opin- ion substantial, and reached the goal of reproducing known puckering free energy differences while keeping other properties, such as inter-molecular interactions and the rotameric distri- bution of the hydroxymethyl group, unchanged. These modifications to the gromos force field will allow to perform more realistic simulations of d- aldopyranoses. They represent an certain improvement in the study of carbohydrate equilibrium properties, but will have an even more important impact on the evaluation of out-of-equilibrium properties, such as in the case of simulated AFM pulling experiments. 

Still, much has to be done regarding the puckering properties of carbohydrates. In par- ticular, the role of skew conformations — possibly detected in the NMR experiments of Snyder and Serianni 67 but not significantly present in both the 45a4 and new parameter sets — has to be clarified, and different sugars, such as pyranoses of pentose nature, should be investigated to further test the force field. Eventually, the puckering properties of furanoses should deserve further attention. The gromos force field, however, is not the only one which has been found to be problematic in reproducing proper puckering properties, and for many force fields the investigations of ring conformer populations are scarce, if not missing at all. Our hope is that, beside the usefluness related to the specific case of the gromos force field parametrization, this work could also serve to attract attention to the importance of the puckering problem in carbohydrate simulations, and to stimulate further investigations. 

