Hydrophobic Interaction-Induced Topology-Independent Destabilization of G-Quadruplex

Since the inception of the G-quadruplex (G4), enormous attention has been devoted to designing small molecules which can stabilize the G-quadruplex. In contrast, the knowledge about the molecules and mechanisms involved in the destabilization of G4 is sparse, although it is well recognized that destabilization of G4 is important in neurobiology and age-related genetic issues. In this study, it has been shown that amphiphilic molecules having a long hydrocarbon chain can destabilize G4, regardless of its topology, using various biophysical and molecular dynamics simulation methods. It has been observed that the hydrophobic interaction induced by the long hydrocarbon chain of amphiphilic molecules is the main contributor in triggering the destabilization of G4, although hydrogen bonding by the polar part of the molecules also cooperates in the destabilization process. The experiment and simulation studies suggest that a long hydrocarbon chain containing amphiphilic molecules gets aggregated, and their hydrocarbon chain as well as the polar group intrude in the quartet region from the 5' side and interact with guanine bases as well as nearby loops through hydrophobic and electrostatic interactions, which trigger the destabilization of G4.