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It is clear from the experimental data that melittin interaction, and hence the disruption pathway is a function of membrane composition. A key outcome of the experiments is that in domain separated membranes DMPC:cholesterol 9:1 and DMPC:DMPG 4:1 melittin interacts preferentially with one of the domains. Due to the similarity of the fingerprints to the neat DMPC case, melittin appears to preference the DMPC rich domain. Hence, in a competitive environment, the membrane-inserted state is the lower free energy state for melittin. According to the models outlined above, melittin can follow the fissure pathway in these cases, as in neat DMPC, including up to 4 membrane bound states (unstructured; structured on the surface; membrane penetrated; aggregated). The analysis of the f-D curves suggests that the first stage is a composite of the individually opposing dissipation trends of the population of the two surface bound and the membrane penetrated states, whereas the second stage is the result of crack formation. The membrane remains mostly intact.


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