Molecular Dynamics Simulations on the Coplanarity of Quercetin Backbone for the Antioxidant Activity of Quercetin-3-monoglycoside

Abstract

Flavonoids are a broad class of low molecular weight, secondary plant phenolics characterized by the flavan nucleus. The family includes flavanols, flavanones, anthocyanidines, flavones, and flavonols. Most of the beneficial effects of flavonoids are attributed to their antioxidant abilities. The flavonoids contain a number of phenolic hydroxyl groups attached to ring structures, conferring the antioxidant activity. Among these flavonoid families, flavonols are found in almost every plant. The most commonly occurring flavonols are those with dihydroxylation in the 3' and 4' positions of B ring and the preferred glycosylation site on the flavonoids is the 3 position. It has been reported that the hydroxyl group at position 3 is required for the maximal radical scavenging activity of flavonols. Quercetin is a representative flavonol with high antioxidant activity. Therefore, we focused on the conformation of quercetin and quercetin-3-monoglycoside to investigate the effect of glycosylation of quercetin on their antioxidant activity. Structure-antioxidant activity relationships of flavonoids have been extensively reported. Generally, antioxidant activity depends on the number and positions of hydroxyl groups and other substituents, and glycosylation of flavonoid molecules. Glucose is the most usual sugar residue but others include galactose and rhamnose. Aside from other factors which can affect the activity, it is generally known that glycosylation of flavonoids diminishes their antioxidant activity when compared to the corresponding aglycones, perhaps since this reduces the number of free hydroxyl groups and also the linkage of sugar may hinder access of the free radical scavengers to the radical center. As mentioned above, there are several and complicated factors which affect the antioxidant activity of flavonol. Conjugation between the Aand B-rings permits a resonance effect of the aromatic nucleus that lends stability to the flavonoid radical. van Acker et al. suggested that the removal of the 3 hydroxyl group or other substituents interfere with the coplanarity of the B-ring with the rest of the flavonoid and the ability to delocalize electrons. They calculated the geometry using quantum chemical calculation which cannot include the solvent effects and shows only optimized conformation. The flavonols are conformationally flexible and their conformations are influenced by the intermolecular environment. Thus, a range of torsion angle of backbone can be observed for the same flavonol in different environments. Therefore, we pursue the trajectories during the molecular dynamics simulations in aqueous environment and investigate the coplanarity of quercetin’s backbone and conformations in order to find out the relationship between the conformation and antioxidant activity. It is difficult to compare the antioxidant activities of flavonols between the results of one author and others because of different experimental condition, methods, and skill. Therefore, we selected one reference which use two different methods and obtained similar results. Six flavonols are investigated by molecular dynamic simulations and their chemical structures and abbreviations are shown in Figure 1. Quercetin aglycone has the most potent antioxidant activity in flavonol aglycones. The structure of quercetin was elucidated by crystal and molecular modeling. The exocyclic B ring of quercetin exists in an almost planar conformation with respect to the rest of the molecule. Quercetin not only has 3-hydroxyl group in the C-ring and 3',4'-dihydroxy groups in the B-ring, but also possess the 2,3-double bond in conjugation with 4-oxo function in the C-ring (Figure 1), which are the essential structural elements for potent radical