Simulation studies of permeability and melting behavior in gel-phase lipid bilayers

Emory University, Atlanta GA

Investigators

Abstract

James T. Kindt at Emory University is supported by the Chemical Theory, Models and Computational Methods program in lipid bilayer research. The dramatically different properties of lipid bilayers in the ordered gel phase and the disordered fluid phase (found below and above the transition temperature, respectively) have found applications in thermoresponsive liposome technology. The proposed research activities in the Kindt group will use atomistic molecular dynamics and mixed Monte Carlo/molecular dynamics (MCMD) methods to explore aspects of gel phase structure, dynamics, and thermodynamics relevant to these properties. First, the behaviors of several force-fields will be evaluated for their agreement with x-ray scattering data and experimental gel/fluid transition temperatures. Secondly, hypotheses for origins of the experimentally determined peak in bilayer permeability near the transition temperature will be explored. Comparison of the free energy of ion and small molecule passage through fluid, gel, and interfacial zones of a bilayer at coexistence will be used to test the "leaky interface" explanation, and continuum-based modeling of surface stress relaxation will be used to test the "surface compressibility" explanation. Thirdly, using MCMD, partitioning of lipid "dopants" within the interior and interfaces of gel phase domains will be evaluated. Finally, the dynamics of gel-phase vesicle response to ultrafast temperature jumps will be modeled, in close conjunction with experimental collaborators, using atomistic simulation for sub-microsecond dynamics, coarse-grained simulation for longer-time relaxation, and phenomenological kinetic modeling. Lipid molecules tend to arrange themselves in water into double-layer sheets called bilayers. Living organisms use lipid bilayers to form boundaries between and within cells. Lipids can also be manufactured into nanoscopic capsules (called liposomes or vesicles) to contain a variety of substances, which find uses in biotechnology, drug delivery, cosmetics and personal care products, agriculture and food science. These are useful if the capsules are designed to empty their contents in response to some "switch". Some lipid bilayers have a built-in "switch" in the form of an inherent sensitivity to temperature: changing the temperature from just below to just above a specific "transition temperature" will cause the liposome to undergo a change in state, similar to melting. The transition influences the shape and permeability of liposomes -- below the transition temperature, the liposome will release contents very slowly, while above the transition temperature, molecules can escape more rapidly. For reasons that are not fully understood, the permeability is strongly enhanced at temperatures very near the transition temperature. Research in the Kindt group will use computer models of molecular behavior to investigate the structure of bilayers and liposomes near the transition temperature, where the lipid structure is partially melted and partially solid, to test hypotheses about this enhancement. In conjunction with colleagues who are measuring the rate of vesicle melting in the laboratory, we will also use our simulations to help describe the structure of the lower-temperature phase of the vesicle, which is not uniform and spherical but has facets and ridges, and the factors that determine the rate of the melting transition. The goal is to discover fundamental reasons for observed liposome behaviors, so that these technologies can be approved and applied more broadly. As a secondary product of this research, the Kindt group will produce molecular animations of our simulations to educate students and the public about lipid behavior over the World Wide Web.