Molecular dynamics simulations of the insertion of two ideally amphipathic lytic peptides LK15 and LK9 in a 1,2-dimyristoylphosphatidylcholine monolayer

Abstract

We present here the results of 1-ns molecular dynamics (MD) simulations of two ideally amphipathic lytic peptides, namely LK(15) and LK(9), in a 1,2-dimyristoylphosphatidylcholine monolayer with two different cross-sectional areas per lipid of 80 A(2) (loose film) and 63 A(2) (tight standard film). These peptides are lytic, ideally amphipathic with a minimalist composition L(i)K(j) and the following sequences: H(2)N-KLLKLLLKLLLKLLK-CO-Ph for LK(15) and H(2)N-KLKLKLKLK-CO-Ph for LK(9). From experimental data, LK(15) exhibits an alpha-helical secondary structure, whereas LK(9) was found to form antiparallel beta-sheets at the interface of a DMPC monolayer. Whatever the specific lipid surface is, the two peptides exhibit very different behavior: the alpha-helix inserts deeply into the monolayer whereas the beta-sheeted peptide stays at the surface within the upper polar part of the monolayer. In all cases, a loose monolayer (80 A(2)) results in noticeable artifacts whereas a monolayer with standard specific surface leads to very reliable behavior well in accordance with experimental data. Despite their different insertion depth, the two peptides exhibit identical lytic efficiency. This is very likely a direct consequence of the very strong Van der Waals interactions between the fatty alkyl chains of the lipids and the highly lipophilic lower part of the peptide, resulting in an identical thinning of the two monolayers.

The antibiotic activity of cationic linear amphipathic peptides: lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes

“…Table 3 [columns MDC (minimal deforming concentration) 50 and MDC 100 ] reveals that, consistent with the results of growth inhibition tests, the activity of melittin was matched by LK15(3.6), LK15(W14)(3.6), and to a lesser extent by LK16(W15)(3.0). In contrast, scr-LK15(W14) exhibited a deforming activity about two orders of magnitude weaker and the Dns(LK) n -series peptides were harmless independently of their length.…”

“…Indeed, the transfer of five or more positive charges per molecule from water into the hydrophobic core of the lipid bilayer is energetically extremely unfavourable unless they are properly counterbalanced by a set of negative charges in register with them. Hence, if transient transmembrane bundles of LK peptide helices were to exist, such bundles would be very unstable because of K + /K + electrostatic repulsions [49,50]. It should also be stressed that the α helix LK15(3.6) is anyway too short to span the membrane bilayer hydrophobic core, even in the case of the thinnest A. laidlawii membrane (see Table 4).…”

Membrane insertion of the N-terminal α-helix of equinatoxin II, a sea anemone cytolytic toxin

“…The differential behaviour of the V22W mutant is no longer detected in the monolayer system. This result suggests that the V22W mutant would be able to transfer its N-terminal α-helix with a parallel orientation with respect to the plane of the membrane ( Figure 1C), a preferred orientation in this system due to the lack of half of the bilayer [37]. Thus its decreased rate of haemolysis and permeabilization activity would arise from the inability to insert the α-helix in the perpendicular orientation that would give rise to the oligomeric pores in bilayers ( Figure 1C).…”

“…The N-terminal helix lies parallel to the membrane when interacting with lipid monolayers, a system in which toxins interact with only one hemilayer [14,16,37]. This means that V22W has no difficulties in transferring the N-terminal α-helix in an orientation parallel to the membrane ( Figure 6).…”

Complex formation and vectorization of a phosphorothioate oligonucleotide with an amphipathic leucine‐ and lysine‐rich peptide: Study at molecular and cellular levels

“…8,9 However, a molecular dynamics study described the different behavior of peptides adopting ␣-helix or ␤-sheet conformations when interacting with model membranes. 10 It has been concluded from these theoretical studies that ␣-helical peptides insert deeply in the monolayer, while ␤-sheet peptides stay at the surface. A family of model peptides, designed to generate ideal amphipathic ␣-helices, and formed by two amino acids (leucine: L, lipophilic residue; lysine: K, hydrophilic residue) have been proposed as potential vectors.…”