PNNL

Abstract

Melittin, an anti-microbial peptide, forms pores in biological membranes and triggers cell death. It has been identified as a potential anti-cancer therapeutic agent. However, until recently melittin’s therapeutic application has been prevented because of a compatible delivery machinery to tumor cells was lacking. Recent research showed that applying per?uorooctylbromide- based nanoemulsion particles (PFOB NEPs) enabled speci?c delivery of melittin to the tumor cell and reduced tumor growth. Melittin adsorbed onto the emulsifying phospholipid monolayer of PFOB-NEP. Interestingly, a high concentration of melittin failed to disrupt the phospholipid monolayer of PFOB NEPs. To determine important structural motifs for melittin binding while PFOB NEPs were intact, we ran atomistic molecular dynamics simulations of melittin bound to the surface of a PFOB NEP. The structure was compared to the control simulation of melittin bound to a bilayer that is disrupted by melittin. Melittin interacted with the phospholipid monolayer of the PFOB NEP in a similar manner as with the bilayer with minor differences. First, melittin was deeply buried in the hydrophobic tail region of monolayer, while the depth was attenuated in the PFOB NEP. Helical conformation was the major secondary structure, but its fraction was reduced in the PFOB NEP. The overall pattern for the direct interaction of melittin with surrounding lipids was similar, but the level of interaction was slightly decreased in the PFOB NEP. These results suggest that melittin interacts with the monolayer of PFOB NEP in a way that is similar way to its interaction with bilayers but deeper penetration into the hydrophobic interior is inhibited. This can be the cause the structural differences and lack of monolayer disruption in the PFOB-NEP. Current simulations suffered from strongly favorable interactions between melittin and lipids and care must be taken to draw conclusions regarding the melittin-driven membrane disruption mechanism.