Spectroscopic and Computational Study of Melittin, Cecropin A, and the Hybrid Peptide CM15 Diana E. Schlamadinger Yi Wang J. Andrew McCammon Judy E. Kim 10.1021/jp304021t.s001 https://acs.figshare.com/articles/journal_contribution/Spectroscopic_and_Computational_Study_of_Melittin_Cecropin_A_and_the_Hybrid_Peptide_CM15/2020536 Antimicrobial peptides (AMPs), such as cecropin A from silk moth, are key components of the innate immune system. They are effective defensive weapons against invading pathogens, yet they do not target host eukaryotic cells. In contrast, peptide toxins, such as honeybee melittin, are nondiscriminating and target both eukaryotic and prokaryotic cells. An AMP-toxin hybrid peptide that is composed of cecropin A and melittin (CM15) improves upon the antimicrobial activity of cecropin A without displaying the nonspecific, hemolytic properties of melittin. Here we report fluorescence and UV resonance Raman spectra of melittin, cecropin A, and CM15 with the goal of elucidating peptide-membrane interactions that help guide specificity. We have probed the potency for membrane disruption, local environment and structure of the single tryptophan residue, backbone conformation near the peptide hinge, and amide backbone structure of the peptides in lipid environments that mimic eukaryotic and prokaryotic membranes. These experimental results suggest that melittin inserts deeply into the bilayer, whereas cecropin A remains localized to the lipid headgroup region. A surprising finding is that CM15 is a potent membrane-disruptor despite its largely unfolded conformation. A molecular dynamics analysis complements these data and demonstrates the ability of CM15 to associate favorably with membranes as an unfolded peptide. This combined experimental–computational study suggests that new models for peptide–membrane interactions should be considered. 2015-12-16 21:48:23 Hybrid Peptide CM 15Antimicrobial peptides target host eukaryotic cells cecropin amide backbone structure membrane AMP melittin lipid headgroup region CM 15 UV resonance Raman spectra