The Abu-pocket paradox of the cyclophilin a / cyclosporin a interaction

A detailed analysis of the cyclosporin A (CsA) / cyclophilin A (CypA) interaction based on the ensemble of the available 3D information demonstrates that, although CypAʹs pocket binding the Abu-2 side chain of CsA seems to be large enough to accomodate bulky groups, in fact only unbranched chains bearing polar substituents are accepted due to the steric and physicochemical influence of a water molecule network. Although cyclophilin Aʹs pocket binding the Abu-2 side chain of cyclosporin A seems to be large enough to accomodate sterically demanding groups, in fact only unbranched carbon chains bearing a polar terminal substituent are accepted because of the steric and physicochemical influence of conserved water molecules.