Atomistic and coarse-grained molecular dynamics study of peptide-lipid membrane dissociation

Measuring and characterizing the strength of the interaction between individual proteins and lipid membranes, by means of single molecule experiments, is important for understanding the role of this interaction in cell function. For example, high precision AFM based dynamic force spectroscopy can be used to measure the dissociation force distribution, P(F), of peptides attached to lipid membranes. However, the interpretation of P(F) in terms of the standard Brownian escape process across a free energy barrier is complicated by the existence of several stochastic pathways along which dissociation may proceed. Thus, the barrier height (activation energy), U₀, and the activation length, x₀ , should be regarded as stochastic quantities with yet to be determined probability distribution. Here we show that prior distributions of U₀ and x₀ can be obtained from the potentials of mean force (PMF) calculated from either all atom (AA) or coarse grained (CG) molecular dynamics (MD) simulations. To this end, the PMFs of three Wimley-White pentapeptides (Ac-WLXLL, with guest residues X=R,I and L) interacting with two different lipid bilayers (zwitterionic POPC and charged POPG) are calculated using the umbrella sampling method. First we show that the PMFs from CG MD simulations are comparable to those obtained from AA MD simulations. The former, being almost two orders of magnitude more efficient than the latter, permits the effective calculation of an ensemble of PMFs, and consequently the construction of the probability densities of U₀ and x₀ . Finally, the obtained results are used to interpret P(F) obtained from AFM experiments.