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. 2015 Jun 23;31(24):6615-31.
doi: 10.1021/la504049q. Epub 2015 Feb 20.

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics

Yuan Hu  1 , Sudipta Kumar Sinha  1 , Sandeep Patel  1
Affiliations

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics

Yuan Hu et al. Langmuir. .

Abstract

Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide-lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

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Figures

Figure 1
Figure 1
Snapshots of the evolution of pore formation in DPPC system(top view). The final configurations of each of the 20 umbrella sampling windows are shown in the figure. For the sake of clarity, water and ions are not shown. Lipid headgroups (containing first 4 beads: NC3, PO4, GL1, GL2) are represented as green spheres and tails (contains 8 beads: C1A, C2A, C3A, C4A, C1B, C2B, C3B, C4B) are represented as purple lines.
Figure 2
Figure 2
Two dimensional average number density map, ρ(r, z) of DPPC bilayer system for each of the 20 umbrella sampling windows are shown in the figure. The calculated average value of OP, < ξ > for each window is shown at top of the each panel. The values in the parentheses correspond the reference OP for each window. The value, r=0 corresponds the center of the pore in the lateral dimension, and z=0 represents the center of the bilayer in z dimension.
Figure 3
Figure 3
(A) PMF of the pore formation for DPPC system. The vertical dash lines show the kink position in the PMF at ξ=0.53, and the critical pore formation OP ξ=0.46. (B) Solid line is the change in average lateral area per lipid of DPPC system as a function of the OP and dash line is the fitted polynomial functions of it. Panels (C) and (D) show the correlation between pore formation free energy (ΔG1) and bilayer thickness, and the nucleation free energy (ΔGpore) and bilayer thickness.
Figure 4
Figure 4
(A) PMF of nonaarginine translocation into model DPPC bilayers along the z distance from bulk water to the center of the bilayer. (B) The corresponding value of average pore order parameter, ξ as calculated from all umbrella sampling windows along the peptide translocation path is shown. The inset of the figures highlight the region contains the transmembrane pore.
Figure 5
Figure 5
Snapshots of the nonaarginine translocation at different locations. From Left to right, the configurations correspond the z value of distance between the center of mass of peptide and the center of mass of the bilayer restrained at 0.0, 0.3, 0.5, 2.3, and 6.0 nm, respectively. (A) top view of the DPPC system at those locations. For the sake of clarity, water, ions and peptide are not shown. Lipid headgroups are represented as green spheres and tails are represented as purple lines. (B) side view of the corresponding configurations, Lipid tails are are not shown in the figure. Lipid headgroups are represented as green spheres and peptide Arg9 is represented as blue line, water and ions are represented as red points. Once the pore is formed, water and ions move freely into the pore regions.
Figure 6
Figure 6
Panels (A) and (B) are the correlations of bilayer thickness with PMF for transferring nonaarginine peptide from global minimum to the center of the bilayer (ΔG3) and to the position where nonaarginine induces to form a pore (ΔGpore, kink position in PMF), as obtained from 18 different bilayer systems.
Figure 7
Figure 7
Correlation between nonaarginine induced pore formation PMF (ΔGpore) in peptide containing bilayer system and intrinsic pore formation PMF (ΔGnucl) as obtained from peptide free bilayer system.
Figure 8
Figure 8
Top panel shows the correlation of the PMF (ΔG1) for creating a transmembrane pore of 3nm radius with the area per lipid, lipid thickness and bending rigidity of the bilayers, fallen in class 1. The middle and bottom panels show the same correlation with the intrinsic pore formation PMF (ΔGnucl) and nonaarginine induced pore formation PMF (ΔGpore) for the same bilayer systems. The purple lines with red circle symbol shows the PS lipids, and the green lines with blue square symbol shows the PC lipids.
Figure 9
Figure 9
Correlation between the nonaarginine induced pore formation PMF (ΔGpore) in peptide containing bilayer system and intrinsic pore formation PMF (ΔGnucl) for the bilayer systems in class 1. The purple lines with red circle symbol shows the PS lipids, and the green lines with blue square symbol shows the PC lipids.
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