October 19, 2006, Third Annual PhysChem Symposium, Obernai, France

In Silico Simulation of Compound Polymorphism and Amphipathy in Membrane Absorption and Permeability

Robert Brasseur

Abstract

The distribution of organic molecules, proteins, lipids, peptides and pharmacological agents in cells is accounting for a series of molecules and medium criteria: hydrophobicity, charge and structure complementarity. On one hand, we developed IMPALA, an in silico model of biological membranes to test molecule insertion and permeability. IMPALA mimics different types of membranes taking their composition and (a)symmetry into account. On the other hand, we demonstrated that solubility is related to the hydrophobicity/hydrophily ratio of molecule 3D structures. This ratio is around 1 for soluble proteins. Higher ratio shift the proteins to hydrophobic environments.

We shall show in our conference that net hydrophobicity and charges of molecules depend upon their tridimensional structures. Some molecules can and do change 3D structures in order to adapt to medium properties. Hence molecule solubility and permeability can depend upon a structural adaptability.

A reliable in silico procedure of prediction of 3D structures from structural formulas of organic compounds and from linear sequences of peptides was recently developed in our group. Structures can be predicted in hydrophobic, hydrophilic, and interfacial media. Therefore, we can test membrane insertion and membrane permeability of a molecule by modelling the transmembrane movements of its environment-adapted conformations. This enables us to calculate the optimal energy profile of permeability in many types of membranes and, as a consequence to predict whether the molecule will stay in or off a membrane, and whether it will or will not cross this membrane.

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