Interactions of Amphiphilic Molecules with Membranes
The biophysics of detergent-resistant membranes and ´lipid rafts´
Many studies of functional domains in membranes (lipid rafts) have been based on the assumption that rafts can be isolated from cells as detergent-resistant membrane patches (DRMs). Our work on detergent effects on lipid mixtures has shown that this is not generally justified since the addition of detergents can induce the formation or modification of domains in membranes. Our prediction of detergent-induced domain formation was recently confirmed in vivo ( van Rheenen et al. 2005 Embo J 24:1664 ) and has contributed to a critical review of the raft hypothesis and a new view of biomembrane domains. See also S. Munro (2003, Cell 115:377), McMullen et al. (2004, Curr. Op. Coll. Interf. Sci. 8:459), L. Pike (2006, J. Lipid Res. 47:1597) .
The interaction of drugs with biological and artificial membranes
We are interested in improving and deriving quantitative models describing the interaction of drugs and pharmaceutically relevant compounds with membranes, comprising membrane insertion (partitioning), permeation, release, and additive-induced changes in membrane properties. The project aims at a better understanding of the action of membrane-active compounds and the optimization of drug formulation strategies, including liposomal carriers.
Towards a rational optimization of membrane protein solubilization
Determining and understanding the structure, dynamics and function of membrane proteins is one of the key challenges for biology and pharmacology today. So far, the isolation of membrane proteins in their native, functional state is a great challenge and the choice and optimization of suitable conditions for their solubilization from membranes is highly empirical and time consuming. We aim at further developing the good biophysical understanding of the solubilization of simple, one-component, model membranes (vesicles) to become applicable also for predicting and tuning the solubilization properties of highly complex, biological membranes. Another goal is the adaptation of micellar properties to the needs of both the protein and the method chosen for its characterization.
Development of microcalorimetric assays for colloidal and membrane systems
We have been introducing protocols characterizing the interactions of compounds with membranes by means of isothermal titration calorimetry. These assays provide a detailed thermodynamic characterization of membrane partitioning or binding, permeation, permeabilization, (de)stabilization and solubilization by surfactants and peptides. Recently, we have extended the applicability of these assays to insoluble compounds such as cholesterol. We have also pioneered pressure perturbation calorimetry for studying lipid and surfactant systems and water sorption calorimetry of lipids.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street
Toronto, Ontario, M5S 3M2