Parkson Lee-Gau Chong, PhD
Department of Biochemistry
Center for Substance Abuse Research
Project 1: Bipolar Tetraether Liposomes: Lipid Chemistry, Physical Properties, and Technological Applications
The long-term goals of this research are to understand how the Archaea live in extreme environments and to use the Archaeal bipolar tetraether lipids for technological applications. The Archaea are curious and remarkable organisms; and, their lipids are structurally distinctly different from their bacterial and eukaryotic counterparts. The native habitat of the thermoacidophilic archaeon Sulfolobus acidocaldarius, which is the focus of this research, is hot (65-80 oC) and acidic (pH 2-3) sulfur springs. The plasma membrane of S. acidocaldarius not only serves as a barrier between the low pH extracellular environment and the neutral pH intracellular compartment (pH 6.5), but also performs proton pumping and other cellular activities at high temperatures. The ability of the plasma membrane to achieve these goals in extreme environments is not clearly understood, although there is evidence suggesting that it has something to do with its unique bipolar tetraether lipid structures which contain cyclopentane rings, branched methyl groups, ether linkages, and sugar moieties. The objective of this research is to elucidate the physical origin of the remarkable thermal, chemical, and mechanical stability of the archaeal plasma membrane via a systematic study on the physical properties of liposomes composed of bipolar tetraether lipids (specifically, polar lipid fraction E, PLFE) isolated from S. acidocaldarius. Fluorescence spectroscopy and microscopy, photon correlation spectroscopy, FT-IR, small angle X-ray scattering, high-pressure probe techniques, pressure perturbation calorimetry, differential scanning calorimetry, electron microscopy, proteomics, and molecular modeling are the major tools used in this research. Temperature, pressure, pH and salt concentrations are the experimental variables. Membrane properties being investigated include solute permeability, molecular packing, vesicle fusion, compressibility, free volume and volume fluctuations, lateral diffusion, and protein-lipid interactions. These studies will give molecular insights into the structure-function relationship of thermoacidophilic archaeal membranes and may also lead to the development of PLFE liposomes or films for applications in coating, storage, membrane protein crystallization, and targeted drug delivery. We are currently developing nano-scale archaeosomes to deliver anti-vascular drugs to solid tumors.
Project 2: Sterol Superlattices: physical properties, biological functions, and technological applications
Sterol superlattice is a novel concept for understanding the structural and functional role of cholesterol in membranes. This concept was first proposed from our laboratory in 1994. The current view of sterol superlattice formation is depicted below. The rectangle-like objects represent a lipid membrane, where regular (shaded areas) and irregular (blank areas) regions coexist. In regular regions, sterol molecules are regularly distributed into either hexagonal or centered rectangular superlattices within the host lipid matrix. There is a biphasic change in proportion of irregular region to regular region (R, solid line), membrane free volume (V, solid line), and the perimeter of regular region (P, dashed line) with membrane cholesterol content in the neighborhood of a critical sterol mole fraction Cr (e.g., 20.0, 22.2, 25.0, 33.3, 40.0 and 50.0 mol% sterol in diacylphosphoacylglycerides). The Cr values can be predicted from the sterol superlattice theories. The perimeter of the regular region is proportional to the size of the regular region. Thus the perimeter (P) of the regular regions may increase abruptly at Cr causing a large increase in the interfacial area between the regular and irregular regions, making sterols at Cr more exposed to the aqueous phase than sterols at non-Cr. We have previously shown that the extent of sterol superlattice regulates the activities of surface acting enzymes (e.g., phospholipase A2 and cholesterol oxidase), drug partitioning into membranes, and free radical-induced sterol oxidation. We will continue to elucidate the importance of sterol superlattice in membrane functions and cellular activities. Our current research addresses the following questions: (1) Do sterol superlattices (from model membrane studies) and membrane rafts (from cell biology studies) share the same physical origin? (2) What is the role of sterol superlattice in signal transduction, lipid metabolism, lipid trafficking, and inflammatory responses? (3) How to use the concept of sterol superlattice to develop new technological applications (a US patent (a sensitive method to assess the potency and possible adverse effects of anti-oxidants) is pending). These studies may shed light on the etiological role of cholesterol in cardiovascular disease, Alzheimer’s disease, cancer, diabetes and other disorders.
Sugar, I.P. and Chong, P.L.-G. (2012) A Statistical Mechanical Model of Cholesterol/Phospholipid Mixtures: Linking Condensed Complexes, Superlattices and the Phase Diagram. Journal of American Chemical Society, 134, 1164-1171.
Chong, P.L.-G., Ayesa, U., Daswani, V., and Hur, E.C. (2012) On Physical Properties of Tetraether Lipid Membranes: Effects of Cyclopentane Rings. Archaea, vol. 2012, Article ID 138439, 11 pages. doi:10.1155/2012/138439.
Zhai, Y., Chong, P.L.-G., Taylor, L.J.A., Erlkamp, M., Grobelny, S., Czeslik, C., Watkins, E., and Winter, R. (2012) Physical Properties of Archaeal Tetraether Lipid Membranes as Revealed by Differential Scanning and Pressure Perturbation Calorimetry, Molecular Acoustics, and Neutron Reflectometry: Effects of Pressure and Cell Growth Temperature. Langmuir, 28, 5211-5217.
Samson, R.Y., Obita, T., Hodgson, B., Shaw, M., Chong, P.L.-G., Williams, R., and Bell, S.D. (2011) Molecular and Structural Basis of ESCRT-III Recruitment to Membranes during Archaeal Cell Division. Molecular Cell, 41, 186-196.
Jeworrek, C., Evers, F., Erlkamp, M., Grobelny, S., Tolan, M., Chong, P.L.-G., and Winter, R. (2011) Structure and Phase Behavior of Archaeal Lipid Monolayers. Langmuir, 27, 13113–13121.
Chong, P.L.-G. (2008) Physical Properties of Membranes Composed of Tetraether Archaeal Lipids. In “Thermophiles: Biology and Technology at High Temperatures”, (Robb, F., Antranikian, G., Driessen, A., and Grogan, D., eds.), CRC Press, FL., pp.75-97.
Chong, P.L.-G., and Olsher, M. (2004) Fluorescence Studies of Lipid Lateral Organization in Liposomal Membranes (review). Soft Materials, 2, 85-105.
Chong, P.L.-G., Zein, M., Khan, T.K., and Winter, R. (2003) Structure and Conformation of Bipolar Tetraether Lipid Membranes Derived from Thermoacidophilic Archaeon Sulfolobus acidocaldarius as Revealed by Small-Angle X-Ray Scattering and High Pressure FT-IR Spectroscopy. J. Phys. Chem. 107, 8694-8700.
Gliozzi, A, Relini, A., and Chong, P.L.-G. (2002) Structure and Permeability Properties of Biomimetic Membranes of Bolaform Archaeal Tetraether Lipids (review). J. Membrane Science, 206, 131-147.
Wang, M.M., Sugar, I.P., and Chong, P.L.-G. (2002) Effect of Double Bond Position on Dehydroergosterol Fluorescence Intensity Dips in Phosphatidylcholine Bilayers with Saturated sn-1 and monoenoic sn-2 acyl chains. J. Phys. Chem. 106, 6338-6345.
Zhou, J.G., Koulas, S., and Chong, P.L.-G. (2000) Shape Memory Alloy Activated High-Pressure Optical Cell for Biophysical Studies. Rev. Sci. Instrum. 71, 4249-4256.