Fig. 17.7 Experimentally determined binding geometries of methotrexate (green carbon atoms) and dihydrofolate (gray carbon atoms) in dihydrofolate reductase. The heterocycles of the ligands are bound through H-bonds to the carboxylate or carbonyl group of an amino acid that is oriented into the binding pocket. Two water molecules (red spheres) mediate additional H-bonds between the ligands and the protein. The difference in the binding mode that is discussed in Fig. 17.6, is clearly recognized. On the right-hand side the electrostatic potentials around methotrexate (top) and dihydrofolate are shown. The molecules are found in a spatial orientation that was determined by crystal structure analysis. Considered qualitatively, the electrostatic potentials of both molecules in this orientation have very similar form.