Free Energy Profile of the Interaction between a Monomer or a Dimer of Protegrin-1 in a Specific Binding Orientation and a Model Lipid Bilayer

Abstract

The free energies of adsorption of the monomer or dimer of the cationic β-hairpin antimicrobial peptide protegrin-1 (PG1) in a specific binding orientation on a lipid bilayer are determined using molecular dynamics (MD) simulations and Poisson-Boltzmann calculations. The bilayer is composed of anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) and palmitoyl-oleoyl-phosphatidylethanolamine (POPE) with ratio 1:3 (POPG:POPE). PG1 is believed to kill bacteria by binding on their membranes. There it forms pores that lyse the bacteria. Herein we focus on the thermodynamics of binding. In particular, we explore the role of counterion release from the lipid bilayer upon adsorption of either the monomeric or the dimeric form of PG1. Twenty two 4ns-long MD trajectories of equilibrated systems are generated to determine the free energy profiles for the monomer and dimer as a function of the distance between the peptide(s) and the membrane surface. The MD simulations are conducted at eleven different separations from the membrane for each of the two systems, one with PG1, the second with PG1 dimer only of a specific orientation of the monomer and dimer without taking into account the change of entropy for the peptide. To calculate the potential of mean force for each peptide/membrane system, a variant of constrained MD and thermodynamic integration is used. We observed that PG1 dimer binds more favorably to the POPG:POPE membrane. A simple method for relating the free energy profile to the PG1-membrane binding constant is employed to predict a free energy of adsorption of −2.4 ± 0.8 kcal/mol. A corresponding PG1-dimer-membrane binding constant is calculated as −3.5 ± 1.1 kcal/mol. Free energy profiles from MD simulation were extensively analyzed and compared with results of Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions in a POPG:POPE lipid bilayer.

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

“…However, Vivcharuk and Kaznessis (2010) showed that an AMP dimer has greater peptide-membrane attraction than the monomer counterpart. Therefore, we believe a plausible explanation for our findings is that a dimer/tetramer has a wider, highly positively charged ''carpet-like'' surface leading to increased binding.…”

Strong Electrostatic Interactions Lead to Entropically Favorable Binding of Peptides to Charged Surfaces

“…3. The idea that counter ion release contributes significantly to biomolecular adsorption to a charged surface is well known in the literature, e.g., counter ion release has been shown to drive interactions between proteins and DNA 70 , as well as between peptides and charged lipid bilayers;71 however, as we show below, understanding these contributions on a deeper level allows for greater control over the molecular driving forces in adsorption and thus represents a new step towards rational design of the biomolecule/surface interface. Reweighting Analysis for the Number of Desorbed Ions.…”

Multiscale models of antibiotic probiotics

“…We computed PMFs for PG-1 monomer and dimer adsorption to lipid bilayers (3:1 POPE:POPG) [20], PG-1 dimerization in different environments (water, membrane surface, membrane interior) [21], and studied PG-1 monomer insertion into POPE:POPG lipid bilayers.…”

“…Using atomistic models, we determined the dominant peptide orientations on lipid membranes. We found that electrostatic interactions and counterion release account for the low free energy of peptide-membrane binding [20]. …”

“…PG-1 inserts inside the core of a lipid bilayer with a free energy of approximately −18 kcal/mol [20]. We determined that hydrophobic interactions and ion-bridges between peptide arginines, solution chloride ions and lipid phosphate groups are largely responsible for the peptide insertion.…”