Chapter 3 Insights from Computer Simulations into the Interaction of Small Molecules with Lipid Bilayers

Abstract

The chapter presents a discussion on insights from computer simulations into the interaction of small molecules with lipid bilayers. Ernest Overton's hypotheses about the distribution of small solute molecules in biological membranes and their permeation across these membranes are notable. The Meyer–Overton relationship for anesthetics has probably been influential. The correlation between the potencies of anesthetic compounds and their solubilities in olive oil, considered a model of the membrane interior, was found to be remarkably accurate for all conventional anesthetics and for different animals. The chapter presents a brief description of the methods of molecular simulations used to study the interactions of solutes with membranes. The chapter also discusses the distribution of anesthetics in the lipid bilayer and the mechanisms by which nonelectrolytes permeate membranes. The method of choice for computational studies of membrane systems at a molecular level has been the molecular dynamics method. Computer simulations reveal that solutes are distributed nonuniformly in a membrane and that their permeation across the bilayer cannot be characterized by a single diffusion coefficient. Instead, it is more appropriate to consider the membrane as consisting of at least three different regions comprising, respectively, lipid head groups, rigid hydrocarbon chain segments adjacent to the head groups, and fluid hydrocarbon tails in the center of the bilayer.