Systematic identification of dominant quercetin conformers with radical-scavenging properties

Quercetin, a widely studied dietary flavonoid, exhibits potent bioactivities. However, its radical scavenging behavior has been described inconsistently throughout previous computational studies, largely due to arbitrary selection of a single computational conformer assumed to adequately capture the overall features. To address this issue, we conducted a systematic conformational search to identify the energetically dominant conformational ensemble of quercetin, followed by a comprehensive analysis of its intramolecular interaction patterns, electronic properties, and thermodynamic characteristics. Structural and intramolecular interaction analyses indicate these energetically dominant conformers share a common molecular framework. All adopt a largely planar backbone stabilized by attractive van der Waals interactions, wherein the ether oxygen and the 3-OH group independently form contacts with adjacent aromatic hydrogens on the B ring. Additionally, the 3-OH and 5-OH groups are conformationally constrained by strong hydrogen-bonding interactions with the carbonyl moiety. Despite variations in the orientations of hydroxyl groups at the remaining positions, these conformers display highly similar electronic and reactive properties. Although subtle differences are observed in their calculated thermodynamic preferences across reaction modes, the overall trends remain consistent, with the para-hydroxyl group of the catechol group emerging as the most favorable reactive site. Collectively, the present work provides a reliable basis for representative conformer selection in future quantum-chemical investigations of quercetin antioxidant behavior. Moreover, the results reconcile previously reported discrepancies from the perspective of the dominant conformers ensemble, demonstrating that variations in intramolecular hydrogen-bonding patterns are a major origin of the inconsistent reactive-site rankings reported in earlier studies.