Prediction of binding free energy for adsorption of antimicrobial peptide lactoferricin B on a POPC membrane

Abstract

Molecular dynamics (MD) simulations are used to study the interaction of a zwitterionic palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with POPC is used as a model system for studying the details of membrane-peptide interactions, with the peptide selected because of its antimicrobial nature. Seventy-two 3 ns MD simulations, with six orientations of LFCinB at 12 different distances from a POPC membrane, are carried out to determine the potential of mean force (PMF) or free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the PMF for this relatively large system a new variant of constrained MD and thermodynamic integration is developed. A simplified method for relating the PMF to the LFCinB-membrane binding free energy is described and used to predict a free energy of adsorption (or binding) of -1.05+/-0.39 kcal/mol , and corresponding maximum binding force of about 20 pN, for LFCinB-POPC. The contributions of the ions-LFCinB and the water-LFCinB interactions to the PMF are discussed. The method developed will be a useful starting point for future work simulating peptides interacting with charged membranes and interactions involved in the penetration of membranes, features necessary to understand in order to rationally design peptides as potential alternatives to traditional antibiotics.

Membrane Association of the Diphtheria Toxin Translocation Domain Studied by Coarse-Grained Simulations and Experiment

“…3)" rend="display" xml:id="FD3">$$K=\frac{1}{false(l-l^{\prime }false)}{\int }_{l^{\prime }}^l{\mathrm{italicdze}}^{-w(z)/k_{B}T},$$ where w ( z ) = 0 is assumed for the unbound macrostate as described in detail by (Vivcharuk et al, 2008). The integral over the bound macrostate goes from l′ = 30 Å to l = 51 Å.…”

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

“…In 29 and15 the position, PMF, W ( z ), was evaluated from the orientational PMF, W ( z ,Ω), where Ω is the vector of rotational degrees of freedom. It was found that the orientational PMF, has no strong dependence on the rotation around space-fixed axes y with the origin at the peptide center of mass.…”

“…To find the PMF, W ( D ), from the simulation, we apply the force method which was developed for the PMF calculation of a peptide in the vicinity of a neutral POPC membrane 29 and charged POPG membrane; 15 it is a variant of constrained MD and thermodynamic integration. 30–35 More specifically, we use the relation F̄ ( D ) = −∂ W ( D )/∂ D , where F̄ ( D ) is the mean force (which is in z -direction by symmetry) on the peptide for fixed D .…”

“…For the calculation of the equilibrium binding constant K = ρ B / ρ F and related adsorption free energy Δ G 0 we use 29 …”

Scattering Density Profile Model of POPG Bilayers As Determined by Molecular Dynamics Simulations and Small-Angle Neutron and X-ray Scattering Experiments

“…2,3 However, for the simulation to make any kind of prediction, an accurate structure of the lipids making up the membrane is needed. When such a structure is not available, as is usually the case, the atomÀatom potential interaction parameters producing the inputted lipid structure can be "tweaked" to improve the fit between simulated and experimental data.…”