Dissertation: On the functional ordering of biomembranes : Implications for drug binding

05.03.2010

In his doctoral thesis in the field of biomedicine, Mikko Parry (University of Helsinki) investigated the physicochemical properties of membrane lipids and the thermal behavior and self assembly of charged and uncharged membrane assemblies. Resources of CSC — IT center for science were utilized in the studies.

    Siramesine © Mikko Parry

Cells are packed with membrane structures, defining the inside and outside, and the different subcellular compartments. These membranes consisting mainly of phospholipids have a variety of functions in addition to providing a permeability barrier for various compounds. These functions involve cellular signaling, where lipids can act as second messengers, or direct regulation of membrane associating proteins.

In his study, Parry focuses on relating some of the physicochemical properties of membrane lipids to the association of drug compounds to membranes. A fluorescence based method is described allowing for determination of the membrane association of drugs. This method was subsequently applied to a novel drug, siramesine, previously shown to have anti-cancer activity. Siramesine was found to associate specifically with a signal lipid, phosphatidic acid. This interaction was modeled by a MD simulation. Parry also studied the thermal behavior and self assembly of charged and uncharged membrane assemblies.

The commonly used membrane models, large unilamellar vesicles (LUV) and multilamellar vesicles (MLV) were found to possess different biophysical properties as interlamellar interactions of MLVs drive segregation of a pyrene labeled lipid analogue into clusters. The effect of a counter-ion lattice on the self assembly of a cationic gemini surfactant was studied. The presence of NaCl strongly influenced the thermal phase behavior of M-1 vesicles, causing formation of giant vesicles upon exceeding a phase transition temperature, followed by a subsequent transition into a more homogenous dispersion.

Understanding the underlying biophysical aspects of cellular membranes is of fundamental importance as the complex picture of the structure and function of cells is evolving. Many of the cellular reactions take place on membranes and membranes are known to regulate the activity of many peripheral and intergral membrane associating proteins. From the point of view of drug design and gene technology, membranes can provide an interesting target for future development of drugs, but also a vehicle sensitive for environmental changes allowing for encapsulating drugs and targeting them to the desired site of action.

More information:

Mikko Parry, mikko.parry@helsinki.fi

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