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The University of Southampton
Chemistry

Research project: Essex: The simulation of biological membranes

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The biological membrane is a critical component of all living systems, and plays a particularly important role in regulating the biological activity of pharmaceutical compounds – all drugs have to pass through cell walls to reach their binding sites.

Although conventional Quantitative Structure Activity Relationships based on, for example, polar surface area, show a reasonable correlation with permeability for drug molecules, these relationships do not always apply. Increasing the complexity of the model by explicitly simulating the permeation process is one solution to this problem. We have, therefore, been applying computer simulation methods to study small molecule and drug permeation through model membranes. These simulations have reproduced the observed permeabilities for the small molecules (J. Phys. Chem. B 108, 2004, 4875-4884), and the ability of the simulation to separate the diffusion effects from the thermodynamic contributions to permeability has resulted in a re-assessment of the experimental data (Biophys. J. 87, 2004, 1-13). Insights into the mechanisms underlying drug permeation have also been obtained (BBA – Biomembranes 1718, 2005, 1-21).These calculations therefore offer the possibility of using simulations not only to predict how a drug binds to its receptor, but also to understand the important process of how readily the drug reaches this target.

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Modelling membrane systems using atom-based potentials is, however, very computationally demanding. To address this issue, and ultimately to increase the size of simulation system that may be studied, we have developed a simplified model of the membrane environment, based on the Gay-Berne model of liquid crystals (J. Phys. Chem. B 112, 2008, 802-815). Unlike many other coarse-grain models, our approach is able to quantitatively predict many membrane properties. Of particular note is the successful reproduction of the lateral stress profile across a self-assembled phospholipid bilayer, showing that the essential physics governing bilayer formation has been captured. This model is now being extended to simulate lipid mixtures, with particular emphasis on tackling the problem of biologically important lipid rafts. We have also extended the model to allow the simulation of atomistic small molecules in the membrane (J. Phys. Chem. B 112, 2008, 657-660). This multiscale method is able to reproduce the membrane permeabilities of small molecules, and will be extended to modelling larger membrane-bound proteins.

Related research groups

Computational Systems Chemistry
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