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We previously reported that a series of gangliosides inhibited the activity of an enzyme NAD glycohydrolase (CD38), and that those with tandem sialic acid residues in the sugar chain had great inhibitory effect. We describe the results of computer simulations on three-dimensional and electronic structures of gangliosides to clarify the causative factors of difference in the inhibitory effect and the recognition mechanisms of the enzyme. We found that dipole moments and HOMO were correlated with inhibitory effect by conformational analyses and molecular orbital (MO) calculations. CD38 is likely to recognize the two carboxyl groups in tandem sialic acid residues of gangliosides, as well as the phosphate groups in NAD. A strong correlation was found between the orbital energies of HOMO by MO calculations and the extent of the inhibitory effect. Salvation effects were also considered to interpret the substrate recognition mechanisms in the biological system, which supported the above results.