(261d) Curvature and Tension Effects On the Sorting of Proteins in Phase-Separated Model Lipid Bilayers

The composition of lipid membranes greatly influences both their organization and properties. Highly organized assemblies of proteins and lipids in the membrane, sometimes called “lipid rafts”, have been studied significantly for their evident medical importance due to the promotion of lateral segregation of proteins on the cell surface [K. Simons and R. Ehehalt, J. Clin. Invest., 110, p.597  (2002)].  Experimental model membranes containing cholesterol, dipalmitoyl-phophatidylcholine (DPPC), and dioleoylphosphatidylcholine (DOPC) are known to phase separate into liquid-ordered (lo) and liquid-disordered (ld) phases [S.L. Veatch and S.L. Keller, Biochimica et Biophysica Acta, 1746, p. 172 (2006)].  It has long been hypothesized that certain proteins and lipid chain anchors would be enriched, either in the lo or in the ld phase, thereby increasing their efficacy. We use this model system to calculate the partition coefficient (mole fraction in the lo phase to the mole fraction in the ld phase) of proteins within the phase separated model system.

Using a theoretical model of a bilayer membrane containing cholesterol, DPPC, and DOPC that qualitatively reproduces phase diagrams of giant unilaminar vesicles (GUVs) of the same three components [R. Elliott, I. Szleifer, and M. Schick, Phys. Rev. Lett., 96, p.098101 (2006)], we calculate how the curvature of lipid vesicles determines the amount of binding of molecules with lipid tail anchors.  By explicitly determining the chemical potential difference of species across a curved bilayer under different modes of deformation in both lo and ld phases, we are able to calculate the equilibrium binding concentrations of lipid tail anchors as a function of membrane curvature, concentration of lipids, and solution environment.  Our results are in excellent agreement with recent experiments [N. S. Hatzakis et. al., Nature Chem. Bio., 5, 835, 2009]. We also calculate the partition coefficients of protein chain anchors into lo and ld phases as a function of curvature, surface tension, temperature, and degree of saturation of the chain anchors. We are able to 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.