Molecular dynamics study of an alpha-cyclodextrin-phosphatidylinositol inclusion complex

Cyclodextrins are cyclic oligosaccharides known for their ability to include substrate molecules in their hydrophobic cavity. Moreover, cyclodextrins show a hemolytic activity when mM concentrations are added to blood. This hemolysis is commonly interpreted as a massive dissociation of phospholipids from the cell membrane due to the formation of complexes with the cyclodextrins. In the literature, a complexation between alpha-cyclodextrin (alpha CD) and phosphatidylinositol (PI) specific to the inositol headgroup has been proposed. But the need for the detailed interaction mechanism between the two molecules motivated the present work based on molecular dynamics simulations. Investigation of long range electrostatic interactions shows that a mutual approach of the molecules is only possible when the primary hydroxyl side of alpha CD faces the inositol headgroup of PI. This orientation is also the most favourable from adiabatic-and free-energy profiles calculated along a reaction coordinate that leads to an inclusion of PI into alpha CD. For free energy simulations, partial hydration of the model has been used. A study of glycosidic bond dihedral angles in alpha CD shows an increase in dihedral fluctuations before complexation and a dihedral "freezing" once the complex is formed.