Evaluation of carbohydrate molecular mechanical force fields by quantum mechanical calculations Original Research Article

A quantitative evaluation of 20 second-generation carbohydrate force fields was carried out using ab initio and density functional methods. Geometry-optimized structures (B3LYP/6-31G(d)) and relative energies using augmented correlation consistent basis sets were calculated in gas phase for monosaccharide carbohydrate benchmark systems. Selected results are: (i) The interaction energy of the α-d-glucopyranose·H2O heterodimer is estimated to be 4.9 kcal/mol, using a composite method including terms at highly correlated (CCSD(T)) level. Most molecular mechanics force fields are in error in this respect; (ii) The 3E envelope (south) pseudorotational conformer of methyl 5-deoxy-β-d-xylofuranoside is 0.66 kcal/mol more stable than the 3E envelope (north) conformer and the α-anomer of methyl d-glucopyranoside is 0.82 kcal/mol more stable than the β-anomer; (iii) The relative energies of the (gg, gt and tg) rotamers of methyl α-d-glucopyranoside and methyl α-d-galactopyranoside are (0.13, 0.00, 0.15) and (0.64, 0.00, 0.77) kcal/mol, respectively. The results of the quantum mechanical calculations are compared with the results of calculations using the 20 second-generation carbohydrate force fields. No single force field is consistently better than the others for all the test cases. A statistical assessment of the performance of the force fields indicates that CHEAT(95), CFF, certain versions of Amber and of MM3 have the best overall performance, for these gas phase monosaccharide systems.