Differential Interaction of Antimicrobial Peptides with Lipid Structures Studied by Coarse-Grained Molecular Dynamics Simulations

Abstract

In this work; we investigated the differential interaction of amphiphilic antimicrobial peptides with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid structures by means of extensive molecular dynamics simulations. By using a coarse-grained (CG) model within the MARTINI force field; we simulated the peptide-lipid system from three different initial configurations: (a) peptides in water in the presence of a pre-equilibrated lipid bilayer; (b) peptides inside the hydrophobic core of the membrane; and (c) random configurations that allow self-assembled molecular structures. This last approach allowed us to sample the structural space of the systems and consider cooperative effects. The peptides used in our simulations are aurein 1.2 and maculatin 1.1; two well-known antimicrobial peptides from the Australian tree frogs; and molecules that present different membrane-perturbing behaviors. Our results showed differential behaviors for each type of peptide seen in a different organization that could guide a molecular interpretation of the experimental data. While both peptides are capable of forming membrane aggregates; the aurein 1.2 ones have a pore-like structure and exhibit a higher level of organization than those conformed by maculatin 1.1. Furthermore; maculatin 1.1 has a strong tendency to form clusters and induce curvature at low peptide-lipid ratios. The exploration of the possible lipid-peptide structures; as the one carried out here; could be a good tool for recognizing specific configurations that should be further studied with more sophisticated methodologies.

Keywords: aurein; coarse-grain; helicoidal peptides; lipid bilayers; maculatin; molecular dynamics.

Figure 1

Pairwise alignment (A) of aurein 1.2 and maculatin 1.1 sequences, and helical wheel projections for aurein 1.2 (B) and maculatin 1.1 (C). Residues are colored according to their chemical character as follows: acidic (blue), basic (red), non-polar (yellow), and polar (green).

Figure 2

Schematic representation of the three initial simulated states: soluble peptides near to the lipid bilayer interface (A); peptides at the hydrophobic core region of the membrane (B); and an all-random distribution of the molecules in the simulation box (C).

Figure 3

Electronic density profile (EDP) for aurein systems of the -out (A) and -in (B) cases. The aurein distribution, shown in blue, as magnified 10×. Water and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) distributions are depicted in black and red, respectively.

Figure 4

The small-out aurein system. Isolated molecules of aurein quickly interact with the lipid–water interface, laying over it with a well-defined orientation: hydrophilic residues (green) are facing the water, and the non-polar ones are orientated to the bilayer core. This kind of behavior was present in all of the simulations with aurein when the molecules are isolated.

Figure 5

Small-in aurein system and the pore-like structure. Snapshots from a frontal plane (A) and over the XY bilayer plane (B). Green balls represent polar amino acids, while the red balls represent the non-polar amino acids.

Figure 6

Representative snapshots of Aurein-self simulations: Self-A (A), Self-B (B) and Self-C (C) cases, respectively.

Figure 7

Electron density profiles (EDP) system profile (A) of aurein-in case, calculated over the last 400 ns of the run. Amino terminals (blue) and carboxyl terminals (green) show preferential position at the Z-axis. Water and POPC molecules are depicted in black and red, respectively. Cumulative distribution function (B) for the aurein peptide angle with respect to the Z-axis. A non-linear regression with a three-term equation was performed. Two angle populations (red and blue lines) and a third of randomly-distributed angles (green) were identified.

Figure 8

Electron density profiles as function of Z. Lipid, maculatin, and water are shown in red, blue, and black, respectively. (A) maculatin-out (C) maculatin-in. Representative Snaphots of the systems are shown in (B) maculatin-out and (D) maculatin-in.

Figure 9

Snapshot of the in-B system: two maculatin clusters were observed.

Figure 10

Maculatin-self simulations self-A, self-B, and self-C ((A)–(C), respectively).Peptide chains are depicted in different colors. Water was removed for visualization purpose.