(567bl) Interaction Studies of Small Cationic Cell Penetrating Peptides with Model Cell Membranes Conference: AIChE Annual MeetingYear: 2010Proceeding: 2010 AIChE Annual MeetingGroup: Food, Pharmaceutical & Bioengineering DivisionSession: Poster Session: Bioengineering Time: Wednesday, November 10, 2010 - 6:00pm-8:00pm Authors: Ye, G., University of Rhode Island Gupta, A., University of Rhode Island Parang, K., University of Rhode Island Bothun, G. D., University of Rhode Island Mandal, D., University of Rhode Island Cell penetrating peptides can traverse plasma cell membranes, which allows them to act as delivery vehicles for therapeutic molecules and as scaffolds for developing new antibiotics. We have previously introduced a series of linear peptide analogs (LPAs) comprising of three amino acids, arginine, arginine and lysine, linked through hydrophobic alkyl chains of varying length, Cn= 4, 7 and 11.1 The LPAs were designed based on the binding pocket of Src SH2 domain and synthesized using Fmoc solid phase chemistry. Previous studies with a model bacterial membrane (dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol, DPPC/DPPG (85/15)) confirmed that the more amphiphilic LPA-C11 bound strongly to the bilayers, causing bilayer thinning, vesicle fusion, and significant changes in lipid phase behavior and permeability 2.Our studies have been extended to the model mammalian membrane, dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylserine (DPPC/DPPS (85/15)). Differential scanning calorimetry (DSC) analysis showed phase separation and domain formation corresponding to DPPC-rich and DPPS-rich regions by preferential binding of the LPAs to the charged DPPS lipids. Short chain LPAs (C4 and C7) acted at the bilayer/water interface while the long chain LPA (C11) penetrated into the bilayer. Cryogenic transmission electron microscopy (cryo-TEM) studies showed that LPA-C11 ruptured the vesicles and led to the formation of disks like structures, which was further confirmed by carboxyfluorescein leakage assays. This work shows that the membrane activity of small, water-soluble cationic LPA peptides can be manipulated by changing their hydrophobic/charge balance. 1. Ye, G.; Nam, N. H.; Kumar, A.; Saleh, A.; Shenoy, D. B.; Amiji, M. M.; Lin, X.; Sun, G.; Parang, K., Synthesis and evaluation of tripodal peptide analogues for cellular delivery of phosphopeptides. J. Med. Chem. 2007, 50 (15), 3604-17. 2. Ye, G.; Gupta, A.; DeLuca, R.; Parang, K.; Bothun, G. D., Bilayer disruption and liposome restructuring by a homologous series of small Arg-rich synthetic peptides. Colloids Surf B Biointerfaces 2010, 76 (1), 76-81.