Another MD simulation study by investigated the thermodynamics of polymyxin penetration into the bacterial membrane, employing a more realistic model of the outer membrane. Their energy profile revealed a shallow energy minimum at the interface between the Lipid A headgroup region and bulk water, with an energy maximum occurring deeper in the hydrophobic core of the membrane. This finding is consistent with the hydrophilic nature of both colistin and polymyxin B1. The study also suggested that polymyxins adopt a more folded conformation as they penetrate the membrane, aided by intramolecular hydrogen bonds . This folding behavior is characteristic of macrocyclic peptides, which are known for their "chameleonic" properties-that is, their ability to adapt their conformation to different environmental dielectric constants, a trait that is important for both .