In eukaryotic cells the various membranous organelles have distinct lipid compositions. For example, in the secretion pathway there is a gradient of cholesterol concentration such that the endoplasmic reticulum contains very little cholesterol whereas the plasma membrane typically contains 20 to 40 mol percent cholesterol. Such differences are thought to play critical roles in protein trafficking and sequestering of proteins to specific regions of the membrane, which in turn impact membrane functions such as signal transduction and channel permeability. The focus of our work is to evaluate the role of different bilayer compositions and mechanical properties on the membrane localization and function of physiologically relevant biological molecules.

In the past few years we have been working on three closely related projects: (1) the composition, structure, and properties of membrane microdomains or "rafts", (2) the interactions between cell-lytic peptides and membranes, and (3) the use of bilayer vesicles in drug delivery. In the first project, we have determined that, compared to typical plasma membrane bilayers, membrane rafts are enriched in sphingolipids and cholesterol, are considerably thicker, have different cohesive (elastic) properties, and have quite different free energies of peptide binding. We have found that the unique structural and cohesive properties of rafts can effectively sort transbilayer peptides to different regions of the membrane bilayer. We are currently testing mechanisms by which the cell can sort to rafts lipids involved in signal transduction. In addition, we are in the process of determining whether rafts can concentrate particular protein channels such as connexons and aquaporins to specific membrane regions and thereby regulate their channel properties. The second project involves measuring peptide binding and peptide-induced bilayer leakage for both eukaryotic and bacterial lipids. One goal is to determine how the unique lipopolysaccharides (LPSs) of Gram-negative bacteria impact bacterial susceptibilities to antimicrobial peptides. In the third project we are using; (1) liposomes containing LPS as a basis for a vaccine against endotoxin-related inflammatory reactions and (2) liposomes containing specially designed charged amphiphiles as vehicles for gene delivery to cells.

Selected Publications
McIntosh, T. J. and S. A. Simon. (2006) "Roles of Bilayer Material Properties in Function and Distribution of Membrane Proteins", Annual Review of Biophysics and Biomolecular Structure 35, 177-198.

Vidal, A. and T. J. McIntosh. (2005) "Transbilayer Peptide Sorting Between Raft and Non-Raft Bilayers: Comparison of Detergent Extraction and Confocal Microscopy," Biophysical Journal 89: 1102-1108.

Rajamoorthi, K., H. I. Petrache, T. J. McIntosh, and M. F. Brown. (2005) "Packing and Viscoelasticity of Polyunsaturated _-3 and _-6 Lipid Bilayers as Seen by 2H NMR and X-Ray Diffraction," Journal of the American Chemical Society 127: 1576-1588.

Allende, D., S. A. Simon, and T. J. McIntosh. (2005) "Melittin-Induced Leakage Depends on Lipid Spontaneous Radius of Curvature: Evidence for Toroidal Pores," Biophysical Journal, 88: 1828-1837.

Allende, A. Vidal, and T. J. McIntosh. (2004) "Jumping to Rafts: Gatekeeper Role of Bilayer Elasticity," Trends in Biochemical Sciences (TiBS) 29, 325-330.

Rajamoorthi, K., H. I. Petrache, T. J. McIntosh, and M. F. Brown. (2004) "Packing and Viscoelasticity of Polyunsaturated w-3 and w-6 Lipid Bilayers as Seen by 2H NMR and X-Ray Diffraction," Journal of the American Chemical Society, in press.

Prata, C. A. H., Y. Zhao, P. Barthelemy, Y. Li, D. Lau, T. J. McIntosh, S. J. Lee, and M. W. Grinstaff. (2004) "Charge-Reversal Amphiphiles for Gene Delivery," Journal of the American Chemical Society, 126: 12196-12197.

Tong, J. and T. J. McIntosh. (2004) "Structure of Supported Bilayers Composed of Lipopolysaccharides and Bacterial Phospholipids: Raft Formation and Implications for Bacterial Resistance," Biophysical Journal 86, 3759-3771.

McIntosh, T. J. (2004) "Roles of Bilayer Structure and Elastic Properties in Peptide Localization in Membranes," Chemistry and Physics of Lipids 130, 83-98.

Allende, D., A. Vidal, and T. J. McIntosh. (2004) "Jumping to Rafts: Gatekeeper Role of Bilayer Elasticity," Trends in Biochemical Sciences (TiBS) 29, 325-330.

Tong, J. and T. J. McIntosh. (2004) "Structure of Supported Bilayers Composed of Lipopolysaccharides and Bacterial Phospholipids: Raft Formation and Implications for Bacterial Resistance," Biophysical Journal 86, 3759-3771.

McIntosh, T. J., A. Vidal, and S. A. Simon. (2003) "Sorting of Lipids and Peptides Between Detergent Soluble Bilayers and Detergent Resistant Rafts," Biophysical Journal 85, 1656-1666.

Gandhavadi, M., D. Allende, A. Vidal, S. A. Simon, and T. J. McIntosh. (2002) "Structure, Composition, and Peptide Binding Properties of Detergent Soluble Bilayers and Detergent Resistant Rafts," Biophysical Journal 82, 1469-1482.

Current projects
Sid Simon (Faculty collaborator, Neurobiology): Peptide-lipid interactions, membrane rafts.

Evan Evans (Faculty Collaborator, University of British Columbia): Material properties and permeability of membrane rafts.

Mark Grinstaff (Faculty Collaborator, Boston University Medical Center): Liposomal gene delivery to cells.

Jihong Tong (Research Scientist) Mechanisms of localization of phosphoinositols to rafts.

Adriana Vidal (Research Scientist): Energetics of peptide binding to lipid bilayers, role of cholesterol.