Ab Initio And DFT Studies On Intermolecular Hydrogen Bonds Between Azone And Ceramide

Objective:To investigate the type, strength and nature of the hydrogen-bonding interaction in ceramides and that between Azone and ceramide by modeling N-methylol acetamide(regarded as ceramide) dimer and the dimer of Azacyclopentane-2-one(regarded as Azone)with N-methylol acetamide; to investigate the cooperativity effect and the thermodynamic process between Azone and ceramide by modeling the N-methylol acetamide and Azacyclopentane-2-one(1:2) ternary system; finally to provide theoretical basises of the nature of skin barrier function and the penetration enhancing mechanism of Azone.Methods:On the basis of the theory of ab initio and density functional theory(DFT), all stable complex formations were obtained at B3LYP/6-311++G** level by using Gaussian03package; the hydrogen bond interaction energy of dimer were calculated at B3LYP/6-311++G**, B3LYP/6-311++G(2df,2p), MP2(full)/6-311++G** and MP2(full)/6-311++G(2df,2p) level; the cooperativity effect energy of ternary system were calculated at B3LYP/6-311++G** and MP2(full)/6-311++G** level; the thermodynamic parameters of ternary and the two pathways of ternary formation were got at B3LYP/aug-cc-p VDZ level. The formation rule and the nature of the complex were further revealed by analyses of frequency, NBO(nature bond orbital), AIM(Atoms in Molecules),surface electrostatic potential, energy decomposition, electron density shift, temperature effect and solvent effect.Results:The results showed that strong O–H???O, N–H???O and C–H???O hydrogen bonds could exist in N-methylol acetamide dimer and also exist between azacyclopentane-2-one andN-methylol acetamide. Moreover, the O–H???O and N–H???O hydrogen bonds were stronger than the C–H???O hydrogen bonds. Analyses of frequency, NBO, AIM, surface electrostatic potential, electron density shift confirmed that hydrogen bonds could exist in the dimers;temperature effect and solvent effect show that lower temperature and smaller dielectric constant were benefit to the stability of the dimers. Cooperativity effect and anti-cooperativity were exist in the ternary systems; the change of conformation, the breaking of old hydrogen bonds and the formation of the new hydrogen bonds happened when the ternary system was forming. The thermodynamics calculation showed that the Gibbs free energy changes of the ternary system formation process of the dimer of N-methylol acetamide and Azacyclopentane-2-one followed the N-methylol acetamide were smaller than that of the dimer of N-methylol acetamide followed Azacyclopentane-2-one, but the equilibrium constants became larger.Conclusions:Ceramide molecules could form network structure through O–H???O, N–H???O and O–H???N hydrogen bonds, which may be one of the reasons for the skin stratum corneum preventing outside material into the body. The O–H???O, N–H???O and O–H???N hydrogen bond interactions between Azone and ceramide could change the steric configuration of the ceramide complexes, which may be the reason for Azone promoting drug transdermal absorption. Low temperature and small dielectric constant are benefit to the formation of the two types of hydrogen bonds interaction mentioned above. Cooperativity effect could enhance the interaction between Azone and ceramide on the basis of the original, which may facilitate Azone breaking the 3D network structure of ceramide, and then improved the penetration enhancing ability of Azone. While ternary system formed, Azone prefers to form a dimer with ceramide firstly, then interact with another ceramide rather than interact simultaneously with the dimer of ceramide.