Gangliosides’ Inhibitory Effects on NAD Glycohydrolase: Estimating the Solvation Effect in the Physiological Environment

Abstract

Abstract The solvation effect was considered in order to interpret the causative factors of the differences in gangliosides’ inhibitory effects on CD38, an enzyme nicotinamide adenine dinucleotide (NAD) glycohydrolase, as well as the mechanisms by which the gangliosides recognize CD38, in the biological system. We applied the two-layered our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method as well as the supermolecule method to a large solvated system. For comparison, the conductor-like screening model (COSMO) was applied to the same system. The orbital energy of the highest occupied molecular orbital (HOMO) was correlated with the strength of the gangliosides’ inhibitory effect in both the supermolecule and ONIOM methods; this agrees with our previous results in the gas phase. Solvation only slightly affected both the structures of tandem sialic acid residues themselves and the energy profiles of HOMOs of gangliosides. These results support the previously proposed recognition mechanism, in which CD38 is likely to recognize the two phosphate groups in the substrate, NAD, as well as the two carboxyl groups in gangliosides’ tandem sialic acid residues.