Interactions between fengycin and model bilayers quantified by coarse-grained molecular dynamics

Abstract

Bacteria, particularly of the genus Bacillus, produce a wide variety of antifungal compounds. They act by affecting the lipid bilayers of fungal membranes, causing curvature-induced strain and eventual permeabilization. One class of these, known as fengycins, has been commercialized for treating agricultural infections and shows some promise as a possible antifungal pharmaceutical. Understanding the mechanism by which fengycins damage lipid bilayers could prove useful to the future development of related antifungal treatments. In this work, we present multi-microsecond-long simulations of fengycin interacting with different lipid bilayer systems. We see fengycin aggregation and uncover a clear aggregation pattern that is partially influenced by bilayer composition. We also quantify some local bilayer perturbations caused by fengycin binding, including curvature of the lipid bilayer and local electrostatic-driven reorganization.

Figure 1

(A) Chemical structure of our fengycin of interest. Also shown are space-filling representations shown from the top and side of fengycin with (B) all-atom resolution and our (C) coarse-grained representation. (For the all-atom model, the atoms are colored using green for carbons, white for hydrogens, red for oxygens, and blue for nitrogens. In the coarse-grained model, yellow is used for tail beads, green for peptide backbone beads, and white for amino-acid side chains. In both representations, a black backbone trace of the coarse-grained model is shown for reference.)

Figure 2

Normalized density of each fengycin residue relative to the phosphate density peak for the DPPC systems with one fengycin. (Solid and dashed lines represent residues with peaks below or above the phosphate peak, respectively.) Also shown is a snapshot from a simulation of the fengycin peptide that fits the distribution in the plot (backbone beads are shown as spheres; residues colored to match). Standard error was no larger than 1% at any point (omitted for clarity).

Figure 3

Average number of aggregates of fengycin over time for the systems with 13 fengycins stabilized. To see this figure in color, go online.

Figure 4

Bead-bead contact maps between clustered fengycins for (A) DPPC, (B) POPC, and (C) POPE/POPG bilayers. Residue sequences are shown as axes, with the complete coarse-grained bead list for the peptide portion of fengycin to the right. (D) Also shown are two different views for a representative cluster (palmitoyl chains in yellow, backbones in green, side-chain tyrosine in gray, and the three beads that make up the cyclic-linking tyrosine in blue shades to show the orientation of packing).

Figure 5

Lateral radial distribution of lipids as a function of distance from lipopeptides in the bound leaflet for systems with (A) one fengycin and (B) 13 fengycins. To see this figure in color, go online.

Figure 6

Radial distribution of the headgroup beads of PG and PE lipids relative to the charged beads of (A) Orn², (B) Glu¹, (C) Glu⁵, and (D) Glu⁸ in the POPE/POPG system with one fengycin.

Figure 7

Bilayer curvature indicated by heat maps of phosphate heights relative to neat bilayers and bilayer thickness for clusters of six fengycins and nine fengycins bound to DPPC and POPC bilayers. The X and Y axes are the distance from the centered fengycin cluster (measured in Ångstroms). Extreme values near the origin reflect the fact that there is some occlusion of lipids by fengycin in one or both leaflets. To see this figure in color, go online.

Figure 8

Sample images of curvature induced by nine fengycin clusters in both DPPC and POPC bilayers. (Fengycins are green, lipid tails are yellow, and headgroups for DPPC and POPC are purple and blue, respectively.)

Figure 9

Height of phosphates above the center of the bilayer as a function of distance from the centroid of each fengycin, plotted for both the proximal and distal leaflets (left and right axes, respectively) for the (A) DPPC, (B) POPC, and (C) POPE/POPG systems with 13 fengycins. To see this figure in color, go online.

Figure 10

Principal component-based order parameters for the palmitoyl chains in the three systems, with POPE and POPG shown separately, for the systems with (A) one fengycin and those with (B) 13 fengycins. (Dashed lines indicate the value calculated from equivalent fengycin-free systems.) To see this figure in color, go online.