Relative free energy of binding between antimicrobial peptides and SDS or DPC micelles

Abstract

We present relative binding free energy calculations for six antimicrobial peptide-micelle systems, three peptides interacting with two types of micelles. The peptides are the scorpion derived antimicrobial peptide (AMP), IsCT and two of its analogues. The micelles are dodecylphosphatidylcholine (DPC) and sodium dodecylsulphate (SDS) micelles. The interfacial electrostatic properties of DPC and SDS micelles are assumed to be similar to those of zwitterionic mammalian and anionic bacterial membrane interfaces, respectively. We test the hypothesis that the binding strength between peptides and the anionic micelle SDS can provide information on peptide antimicrobial activity, since it is widely accepted that AMPs function by binding to and disrupting the predominantly anionic lipid bilayer of the bacterial cytoplasmic membrane. We also test the hypothesis that the binding strength between peptides and the zwitterionic micelle DPC can provide information on peptide haemolytic activities, since it is accepted that they also bind to and disrupt the zwitterionic membrane of mammalian cells. Equilibrium structures of the peptides, micelles and peptide-micelle complexes are obtained from more than 300 ns of molecular dynamics simulations. A thermodynamic cycle is introduced to compute the binding free energy from electrostatic, non-electrostatic and entropic contributions. We find relative binding free energy strengths between peptides and SDS to correlate with the experimentally measured rankings for peptide antimicrobial activities, and relative free energy binding strengths between peptides and DPC to correlate with the observed rankings for peptide haemolytic toxicities. These findings point to the importance of peptide-membrane binding strength for antimicrobial activity and haemolytic activity.

Figure 1

IsCT–DPC complex.

Figure 2

An example of a thermodynamic cycle that can be used to compute binding free energy of a peptide to a surfactant micelle.

Figure 3

(a) Time evolution of the positions of the centre of mass of the three peptides with respect to the centre of mass of the SDS micelle. (b) Time evolution of the positions of the centre of mass of the three peptides with respect to the centre of mass of the DPC micelle.

Figure 4

Time evolution of the RMSD from the initial minimised structures for the C_α atoms of the three peptides in the presence of (a) water, (b) SDS and (c) DPC environments, respectively.

Figure 5

The number of clusters of each peptide dihedral angles found in the interval t_ini < t < t_final.

Figure 6

A comparison between the initial minimised structures of the three peptides (top) and the final structures (bottom) as extracted from the last snapshot of each simulation in water, SDS and DPC environments, respectively.

Figure 7

A thermodynamic cycle used to recalculate the relative binding free energy of IsCT analogue, IsCT3.