Although there is now abundant evidence to indicate that membrane models based on bulk solvent analogies are inadequate to explain lipid bilayer transport, no quantitative treatments exist to account for the interfacial, highly ordered nature of bilayers. The long-term aim of this effort is to develop a comprehensive, molecular understanding of solute transport across lipid bilayer membranes using a combination of laboratory experiments, theoretical modelling, and computer simulation. The investigator plans to conduct permeability measurements across liquid crystalline bilayers to account for effects of permeant structure, lipid bilayer structure, and external variables (i.e., temperature, ionic strength, etc.) on permeabilities. Carefully selected model permeants varying in functional group character, molecular size, and shape will be employed to examine the chemical selectivity of bilayers varying in lipid composition and the effects of chain organization of bilayer selectivity to permeant size and shape. Increasing chain order is expected to increase bilayer resistance to transport through effects on both partitioning and diffusion. The investigator expects solute exclusion from the barrier domain to increase with permeant size and bilayer selectivity to molecular to increase with surface density. The investigator plans to develop a unified statistical mechanical theory for partitioning and diffusion of solutes into lipid bilayers to account for the influence of the chain (surface) density on permeabilities. A mean-field model for molecular distribution in lipid bilayers which explicitly considers the reversible work due to volume expansion against a non-uniform lateral pressure and various solute-interphase interactions will be developed. A free volume theory for diffusion in """"""""fluid"""""""" bilayers will be developed based on the hypothesis that the effective displacement of a solute depends on the relative magnitude of solute kinetic velocity and the relaxation frequency of the surrounding lipid chains. A combined algorithm of molecular dynamics and Monte Carlo simulations will be developed to calculate bilayer/water partition coefficients, diffusion coefficients, lateral pressure, and free-volume distribution as a function of depth in the bilayer. Solutes varying systematically in size, shape, and flexibility will be employed in simulations. The results will be used to test the statistical mechanical theory, to establish the functional form of molecular correlation functions, to probe the disturbance of bilayer structure by added solutes, and to explore various diffusion and relaxation mechanisms of solute molecules and free volume in model bilayers. Simulated data will be compared with experiment to determine surface density, solute size and shape-permeability relationships in order to test and modify the theory. The investigator asserts that this proposal represents the first attempt to develop an experimental and theoretical basis for understanding liquid crystalline bilayer permeability which would be both comprehensive and molecular. Inasmuch as the primary function of biological membranes is to control permeation of solutes, such knowledge is essential to understanding cell function and the biological barriers to drug delivery.
