changes should not be sugar-dependent; (c) the changes have to preserve previously known or already tuned molecular properties; (d) the inverted chair free energy of most common sugars (glucose, galactose, mannose) should be higher than 10 kJ/mol; (e) the trend of the inverted chair free energy as a function of the sugar type, as well as (f) the approximate offset between the inverted chair free energies of α and β anomers, have to be reproduced. Within this framework, a complete, quantitative agreement for every sugar type is most probably not feasible, especially given the constraints (a) and (b). However, we found that quite reasonable results can be indeed achieved with minimal parameter changes. Point (a) requires Lennard-Jones parameters and partial charges of the 45a4 parameter set to be preserved. Together with the requirement at point (d), this suggests that only angular or torsional interactions involving three or more ring atoms should be the target of our optimization. This is because among the known properties which are well reproduced by the gromos 45a4 force field there are the rotameric distribution of the hydroxymethyl group and the conformation of the glycosidic linkages (in di-saccharides). We realized quite soon that changing the stiffness of angular interactions did not change the puckering free energy noticeably. Spieser and coworkers 34 showed that the height energetic barrier between $^{4}$C$_{1}$ and $^{1}$C$_{4}$ can be increased by stiffening the angular interactions. However, this affects only the free energy of the transition states, and not the free energy difference of the metastable conformers. Therefore, we concentrated on the torsional interactions, and noticed that every torsional interaction involving three ring atoms (C1,C2,C3,C4,C5 or O5) and either C6 or any hy- droxyl oxygen (O1,O2,O3,O4) was either not present (this is the case of O4–C4–C5–O5, C3–C4–C5–C6, O2–C2–C1–O5, C1–O5–C5–C6 and C5–O5-C1–O1) or present with a phase term cos( δ ) = +1 and multeplicity n = 2 in the torsional potential associated to the dihedral angle φ . As it was pointed out in Ref. 43, such a phase favors the axial conformation of the substituent, with respect to the equatorial one, whereas a negative value of cos( δ ) would favor the equatorial conformation with respect to the axial one. Indeed, one of those interactions (O2–C2–C1–O5) has been eliminated in the 45a4 version of the gromos force field, for the precise purpose of stabilizing the $^{4}$C$_{1}$ conformer. While this is true for glucose, it is not, e.g. , for mannose, whose substituent in C2 is axial in the chair 19 U ( φ ) = k$_{φ}$ [1 + cos( δ ) cos( nφ )] , (10)