Geometry and Stability of Molecular Clusters: Factor to Be Considered in Biomolecular Activity

Betulinic and melaleucic acids, lupan-skeleton triterpenes with very similar structure, present marked differences in anti-malarial activity. While betulinic acid and some of its analogs exhibit strong activity, melaleucic acid is inactive. In the present work, a theoretical approach was used to explain such differences, using Austin Model 1 (AM1) and density functional theory (DFT)/Becke, three-parameter, Lee-Yang-Parr (B3LYP) approaches, and AutoDock Vina calculations. The initial results showed no significant differences between structural and electronic properties. On the other hand, studies of the geometry of molecular clusters with both compounds revealed significant differences. Melaleucic acid clusters were shown to be stable enough to influence the substrate-protein interaction, unlike betulinic acid, which was unable to form clusters comparable to melaleucic acid ones. The present study suggests the molecular clusters as a new factor that has a great influence on the mechanism of biomolecular activity.