Aromatic amino acid residues are often present in carbohydrate-binding sites of proteins. These binding sites are characterized by a placement of a carbohydrate moiety in a stacking orientation to an aromatic ring. This arrangement is an example of CH/pi interactions. Ab initio interaction energies for 20 carbohydrate-aromatic complexes taken from 6 selected ultra-high resolution X-ray structures of glycosidases and carbohydrate-binding proteins were calculated. All interaction energies of a pyranose moiety with a side chain of an aromatic residue were calculated as attractive with interaction energy ranging from -2.8 to -12.3 kcal/mol as calculated at the MP2/6-311+G(d) level. Strong attractive interactions were observed for a wide range of orientations of carbohydrate and aromatic ring as present in selected X-ray structures. The most attractive interaction was associated with apparent combination of CH/pi interactions and classical H-bonds. The failure of Hartree-Fock method (interaction energies from +1.0 to -6.9 kcal/mol) can be explained by a dispersion nature of a majority of the studied complexes. We also present a comparison of interaction energies calculated at the MP2 level with those calculated using molecular mechanics force fields (OPLS, GROMOS, CSFF/CHARMM, CHEAT/CHARMM, Glycam/AMBER, MM2 and MM3). For a majority of force fields there was a strong correlation with MP2 values. RMSD between MP2 and force field values were 1.0 for CSFF/CHARMM, 1.2 for Glycam/AMBER, 1.2 for GROMOS, 1.3 for MM3, 1.4 for MM2, 1.5 for OPLS and to 2.3 for CHEAT/CHARMM (in kcal/mol). These results show that molecular mechanics approximates interaction energies very well and support an application of molecular mechanics methods in the area of glycochemistry and glycobiology.

Department of Biochemistry Institute of Chemical Technology Prague Technická 5 166 28 Prague 6 Czech Republic

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