Energetics and Kinetics of Peptide-Lipid Membrane Interaction: A Molecular Dynamics Study

Abstract

Quantitative characterization of the binding strength of peptides to lipid bilayers is crucial in understanding the molecular mechanism of cellular processes triggered by peptide-lipid interactions. In general, single molecule methods, such as high precision AFM based dynamic force spectroscopy, can be used to measure the dissociation force distribution, P(F), and the corresponding force dependent rupture rate, k(F), of individual peptides bound to a lipid bilayer. However, the interpretation of the results require extensive theoretical and computational modeling that implies the knowledge of the free energy profile (potential of mean force or PMF) of the system as a function of the separation between peptide and membrane surface. To this end, we have used all atom MD simulations, to calculate the PMF of three representative Wimley-White pentapeptides (Ac-WLXLL, with guest residues X=R,I and L) interacting with two different lipid bilayers (zwitterionic POPC and charged POPG). The PMF, as a function of the distance between the residue W and the plane of the membrane, was calculated by using (i) the equilibrium umbrella-sampling method, and (ii) the nonequilibrium FR method. Both methods yielded comparable PMFs. In addition, the FR method also permitted the calculation of the position dependent diffusion coefficient of the peptide. In each case, the values of the activation energy (free energy barrier) and activation length extracted from the PMFs appear to be comparable to previous experimental and computational studies. The obtained energetic and kinetic parameters have been successfully used to fit P(F) and k(F) measured in AFM experiments.