(4bi) Molecular Modeling of Biological Interfaces

This research project is concerned with investigating lipid bilayers and their interactions with various biologically relevant environments. The thermodynamics and kinetics of ordered domain formation in lipid bilayers is studied using a highly detailed three-dimensional molecular theory for the lipids that uses all of the physical conformations along with attractive and electrostatic interactions. The theory captures the shape of experimental phase diagrams of model lipid bilayers of a high melting point saturated lipid, a low melting point unsaturated lipid and cholesterol. Using the theoretically determined phase diagram, the partition coefficients of protein chain anchors into liquid-ordered and liquid-disordered phases is calculated as a function of temperature and degree of saturation of the chain anchor.

Extending this work, we can now take into account the exact molecular architecture of protein chain anchors and calculate the orientations and positions of proteins as they arrange themselves at the order-disorder phase boundary. In addition to providing these insights into important biological processes in the cell membrane, the theory is used to study the effects of tension on phase transitions in lipid bilayers, interleaflet monolayer coupling free energies, using lipids as a platform for biological sensors, and calculating the potential of mean force between transmembrane proteins. Finally, this theory is used in conjunction with current molecular models of micelle and liposome drug delivery devices that take advantage of the physical properties of tumor cells (in particular, over-expressed ligand receptors and excess negative charge from exposed glycolipids on the outer layer of the cell membrane). By putting these two models together, we calculate how the membrane and micelle/drug systems interact with each other in biological environments. Understanding these interactions on a fundamental level allows us to use the combined theory as a design platform for drug delivery applications. We are currently working in collaboration with David Thompson's group at Purdue University to use these design principles in drug delivery devices.