Abstract
The initial steps of membrane disruption by antimicrobial peptides (AMPs) involve binding to bacterial membranes in a surface-bound (S) orientation. To evaluate the effects of lipid composition on the S state, molecular dynamics simulations of the AMPs piscidin 1 (p1) and piscidin 3 (p3) were carried out in four different bilayers: 3:1 DMPC/DMPG, 3:1 POPC/POPG, 1:1 POPE/POPG, and 4:1 POPC/cholesterol. In all cases, the addition of 1:40 piscidin caused thinning of the bilayer, though thinning was least for DMPC/DMPG. The peptides also insert most deeply into DMPC/DMPG, spanning the region from the bilayer midplane to the headgroups, and thereby only mildly disrupting the acyl chains. In contrast, the peptides insert less deeply in the palmitoyl-oleoyl containing membranes, do not reach the midplane, and substantially disrupt the chains, i.e., the neighboring acyl chains bend under the peptide, forming a basket-like conformation. Curvature free energy derivatives calculated from the simulation pressure profiles reveal that the peptides generate positive curvature in membranes with palmitoyl and oleoyl chains but negative curvature in those with myristoyl chains. Curvature inductions predicted with a continuum elastic model follow the same trends, though the effect is weaker, and a small negative curvature induction is obtained in POPC/POPG. These results do not directly speak to the relative stability of the inserted (I) states or ease of pore formation, which requires the free energy pathway between the S and I states. Nevertheless, they do highlight the importance of lipid composition and acyl chain packing.
Similar content being viewed by others
References
Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Micro 3:238–250
Brooks BR et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614
Campelo F, McMahon HT, Kozlov MM (2008) The hydrophobic insertion mechanism of membrane curvature generation by proteins. Biophys J 95:2325–2339
Canham PB (1970) The minimum energy of bending as a possible explanation of the biconcave shape of the human red blood cell. J Theor Biol 26:61–81
Chen Z, Rand RP (1998) Comparative study of the effects of several n-alkanes on phospholipid hexagonal phases. Biophys J 74:944–952
Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092
Evans E, Rawicz W, Smith BA (2013) Back to the future: mechanics and thermodynamics of lipid biomembranes. Faraday Discuss 161:591–611
Fuller N, Rand RP (2001) The influence of lysolipids on the spontaneous curvature and bending elasticity of phospholipid membranes. Biophys J 81:243–254
Fuller N, Benatti CR, Rand RP (2003) Curvature and bending constants for phosphatidylserine-containing membranes. Biophys J 85:1667–1674
Goetz R, Lipowsky R (1998) Computer simulations of bilayer membranes: self-assembly and interfacial tension. J Chem Phys 108:7397–7409
Gruner SM, Parsegian VA, Rand RP (1986) Directly measured deformation energy of phospholipid HII hexagonal phases. Faraday Discuss 81:29–37
Hallock KJ, Lee D-K, Ramamoorthy A (2003) MSI-78, an analogue of the magainin antimicrobial peptides, disrupts lipid bilayer structure via positive curvature strain. Biophys J 84:3052–3060
Helfrich W (1973) Elastic properties of lipid bilayers: theory and possible experiments. Z Naturforsch C 28:693–703
Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697
Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865
Klauda JB et al (2010) Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J Phys Chem B 114:7830–7843
Lagüe P, Roux B, Pastor RW (2005) Molecular dynamics simulations of the influenza hemagglutinin fusion peptide in micelles and bilayers: conformational analysis of peptide and lipids. J Mol Biol 354:1129–1141
Lindahl E, Edholm O (2000) Spatial and energetic-entropic decomposition of surface tension in lipid bilayers from molecular dynamics simulations. J Chem Phys 113:3882–3893
MacKerell AD et al (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616
Méléard P et al (1997) Bending elasticities of model membranes: influences of temperature and sterol content. Biophys J 72:2616–2629
Nagle JF (2013) Introductory lecture: basic quantities in model biomembranes. Faraday Discuss 161:11–29
Nagle JF, Tristram-Nagle S (2000) Structure of lipid bilayers. Biochim Biophys Acta 1469:159–195
Nose S (1984) A unifed formulation of the constant temperature molecular-dynamics methods. J Chem Phys 81:511–519
Perrin BS Jr et al (2014) High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion. J Am Chem Soc 136:3491–3504
Pujals S et al (2013) Curvature engineering: positive membrane curvature induced by epsin N-terminal peptide boosts internalization of octaarginine. ACS Chem Biol 8:1894–1899
Rand RP, Fuller NL, Gruner SM, Parsegian VA (1990) Membrane curvature, lipid segregation, and structural transitions for phospholipids under dual-solvent stress. Biochem 29:76–87
Rawicz W, Olbrich KC, McIntosh T, Needham D, Evans E (2000) Effect of chain length and unsaturation on elasticity of lipid bilayers. Biophys J 79:328–339
Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comp Phys 23:327–341
Safran SA (1994) Statistical thermodynamics of surfaces, interfaces, and membranes. Westview Press, Boulder
Salnikov ES, Bechinger B (2011) Lipid-controlled peptide topology and interactions in bilayers: structural insights into the synergistic enhancement of the antimicrobial activities of PGLa and magainin 2. Biophys J 100:1473–1480
Salnikov ES, Mason AJ, Bechinger B, Salnikov ES, Mason AJ, Bechinger B (2009) Membrane order perturbation in the presence of antimicrobial peptides by H-2 solid-state NMR spectroscopy. Biochimie 91:734–743
Sodt AJ, Pastor RW (2013) Bending free energy from simulation: correspondence of planar and inverse hexagonal lipid phases. Biophys J 104:2202–2211
Sodt AJ, Pastor RW (2014) Molecular modeling of lipid membrane curvature induction by a peptide: more than simply shape. Biophys J 106:1958–1969
Sonne J, Hansen FY, Peters GH (2005) Methodological problems in pressure profile calculations for lipid bilayers. J Chem Phys 122:124903
Strandberg E, Tiltak D, Ehni S, Wadhwani P, Ulrich AS (2012) Lipid shape is a key factor for membrane interactions of amphipathic helical peptides. Biochim Biophys Acta 1818:1764–1776
Strandberg E, Zerweck J, Wadhwani P, Ulrich Anne S (2013) Synergistic insertion of antimicrobial magainin-family peptides in membranes depends on the lipid spontaneous curvature. Biophys J 104:L9–L11
Szleifer I, Kramer D, Ben-Shaul A, Gelbart WM, Safran SA (1990) Molecular theory of curvature elasticity in surfactant films. J Chem Phys 92:6800–6817
Szule JA, Rand RP (2003) The effects of gramicidin on the structure of phospholipid assemblies. Biophys J 85:1702–1712
Venable RM, Luo Y, Gawrisch K, Roux B, Pastor RW (2013) Simulations of anionic lipid membranes: development of interaction-specific ion parameters and validation using NMR data. J Phys Chem B 117:10183–10192
Venable RM et al (2014) CHARMM all-atom additive force field for sphingomyelin: elucidation of hydrogen bonding and of positive curvature. Biophys J 107:134–145
Watson MC, Brandt EG, Welch PM, Brown FLH (2012) Determining biomembrane bending rigidities from simulations of modest size. Phys Rev Lett 109:028102
Wiesner J, Vilcinskas A (2010) Antimicrobial peptides: the ancient arm of the human immune system. Virulence 1:440–464
Wimley WC (2010) Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chem Biol 5:905–917
Zemel A, Ben-Shaul A, May S (2008) Modulation of the spontaneous curvature and bending rigidity of lipid membranes by interfacially adsorbed amphipathic peptides. J Phys Chem B 112:6988–6996
Acknowledgments
This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Perrin, B.S., Sodt, A.J., Cotten, M.L. et al. The Curvature Induction of Surface-Bound Antimicrobial Peptides Piscidin 1 and Piscidin 3 Varies with Lipid Chain Length. J Membrane Biol 248, 455–467 (2015). https://doi.org/10.1007/s00232-014-9733-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-014-9733-1