Quantitative characterization of additivity in peptide-lipid membrane interaction using coarse-grained MD simulations, AFM force spectroscopy, and theoretical modeling

Quantitative assessment of the interactions between peptides and lipid membranes may provide a better understanding of their role in cellular processes. For example, by identifying the available dominant energetic dissociation pathways, one can determine and characterize the attachment strength of the peptide to the lipid membrane. In the present study, we have employed coarse-grained (CG) molecular dynamics (MD) simulations to investigate the conformational dynamics and energetics of Wimley-White polyleucine peptides (Ac-WL_n with n=1,...,6) interacting with POPC lipid membranes. A detailed description of the binding of peptides with different lengths to the lipid membrane was obtained from CG-MD trajectories by calculating the penetration depth distribution of individual residues. Next, utilizing the umbrella sampling method, we calculated an ensemble of potentials of mean force (PMFs) as a function of the peptide-lipid membrane separation. This allowed us to construct the probability densities for both the PMF barrier height (activation energy) and activation length and, thus, identify the dominant dissociation pathways of the peptide from the membrane. Consistent with the experimentally measured bilayer-to-solution free energy of transfer, we found that the mean activation energy scales linearly with the number of L-residues. Finally, the computed PMFs, combined with a recently developed theoretical model, were used to (i) interpret the dissociation force distributions, P(F), determined from high-precision AFM-based dynamic force spectroscopy, and (ii) extract the corresponding intrinsic dissociation rates k₀. A detailed analysis of these results, obtained with a combination of computational, theoretical, and experimental techniques, provides a deeper quantitative insight into the effect of a single residue to the binding and interaction of short peptides with lipid membranes.