Lipid interactions of LAH4, a peptide with antimicrobial and nucleic acid transfection activities

Abstract

The cationic amphipathic designer peptide LAH4 exhibits potent antimicrobial, nucleic acid transfection and cell penetration activities. Closely related derivatives have been developed to enhance viral transduction for gene therapeutic assays. LAH4 contains four histidines and, consequently, its overall charge and membrane topology in lipid bilayers are strongly pH dependent. In order to better understand the differential interactions of this amphipathic peptide with negatively-charged membranes its interactions, topologies, and penetration depth were investigated in the presence of lipid bilayers as a function of pH, buffer, phospholipid head group, and fatty acyl chain composition using a combination of oriented synchrotron radiation circular dichroism spectroscopy as well as oriented and non-oriented solid-state NMR spectroscopy. This combination of methods indicates that in the presence of lipids with phosphatidylglycerol head groups, the topological equilibria of LAH4 is shifted towards more in-plane configurations even at neutral pH. In contrast, a transmembrane alignment is promoted when LAH4 interacts with membranes made of dimyristoyl phospholipids rather than palmitoyl-oleoyl-phospholipids. Finally, the addition of citrate buffer favours LAH4 transmembrane alignments, even at low pH, probably by complex formation with the cationic charges of the peptide. In summary, this study has revealed that the membrane topology of this peptide is readily modulated by the environmental conditions.

Trichogin GA IV Alignment and Oligomerization in Phospholipid Bilayers

“…Upon further increasing the peptide concentration, higher‐order oligomers have been observed (Figure ) . Equilibria connecting different topological and association states have also been observed for other antimicrobial peptides, where hydration, membrane phase, lipid composition, membrane thickness, and the presence of other peptides have all been shown to be important …”

Thermodynamic and Biophysical Analysis of the Membrane-Association of a Histidine-Rich Peptide with Efficient Antimicrobial and Transfection Activities

“…24,25 The interfacial partitioning of the helices explains the disordering of the fatty acyl chains at the hydrophobic core of the membrane, 18,25,26 and the pore forming activities of these peptides. 27,28 All binding parameters deduced with CD spectroscopy for membranes with and without POPS are summarized in Table 1.…”

Structure and membrane interactions of the homodimeric antibiotic peptide homotarsinin

“…This data corroborates the proposed higher membrane-association of Htr discussed earlier. However, both peptides were more active in permeating the zwitterionic POPC when compared to negatively-charged POPC:POPG (3:1) membranes (Supplementary Figure 7) suggesting that although the negative charges increase binding they also trap the homotarsinin peptides in a topology less prone to disrupt the membrane4041. Interestingly, in presence of phosphate buffer a lower percentage and slower kinetics of carboxyfluorescein release were observed for homotarsinin.…”