Interaction of Amphiphilic Molecules with Lipid Bilayers: Kinetics of Insertion, Desorption and Translocation

Abstract

Passive transport across lipid bilayers is a significant, if not dominant, route for the permeation of biologically active amphiphiles through cell membranes. Often, the quantitative description of the rate of permeation is based on a single kinetic parameter, the permeability coefficient. However, the nature of the interactions between amphiphilic molecules and lipid bilayers is complex and involves different steps (insertion, translocation and desorption), which affect both the extent of partition and the rate of permeation. Quantitative knowledge of the rate constants associated with each individual step is required for proper understanding of the whole process, and certainly useful in prediction of the ability of new drug compounds to access the interior of their cell targets. This chapter reviews the formalisms applicable to the kinetics of interaction of small solutes with lipid bilayers. Several important limiting cases, corresponding to different ranges of aqueous solubility and membrane partition, are considered, and selected examples of applications of fluorescence spectroscopy to quantitative description of solute/bilayer interaction are presented. We also address the state of the art regarding methods for calculation of rate constants of solute/lipid interaction and permeability coefficients from molecular dynamics simulations. These methods rely on accurate computation of free energy profiles of solutes across lipid bilayers, and strategies to this purpose, namely employing enhanced sampling of improbable states with the so-called umbrella sampling method, are discussed.