Theoretical and Computational Modeling of the Rupture Force Distribution in Peptide Lipid Interactions

Abstract

Peptide-lipid interactions are essential for understanding various cellular processes and their mechanisms. Both experimental and theoretical study of these interactions is notoriously difficult due to the complexity of the system and the wide range of time and length scales involved. Atomic force microscopy (AFM) based force spectroscopy can be used to quantify the strength of peptide-lipid interactions, at the single molecule level, by measuring the corresponding detachment (last rupture) force F. Based on the experimental and all-atom molecular dynamics simulation results, we argue that the contact between a peptide and lipid membrane right before detachment is localized at the level of one or two residues, in general, situated at the end of the peptide. Thus, we show that the experimentally determined rupture force distribution function, P(F), can be modeled as a weighted combination of several independent escape processes of Brownian particles across free energy barriers. Each detachment pathway is characterized by (i) an energy parameter (barrier height, U0); (ii) a geometric parameter (spatial extent of the potential barrier, x0); and (iii) a kinetic parameter (intrinsic escape rate, k0). While the parameters U0 and x0 are specific to individual residues, k0 and the weight parameters need to be determined through the fitting process. The method has been successfully applied to reproduce the experimentally measured P(F) for several short peptides interacting with model lipid bilayers. Work supported by the Burroughs Wellcome Fund (Career Award at the Scientific Interface), the NSF (CAREER Award #: 1054832), and the MU Research Board. The computation for this work was performed on the HPC infrastructure provided by RCSS at the University of Missouri, Columbia MO. The HPC equipment for the computational work is supported by NSF CNS-1429294.