title: Interactions of cyclosporines with lipid membranes as studied by solid-state nuclear magnetic resonance spectroscopy and high-sensitivity titration calorimetry.
abstract: Cyclosporin A (CyA) interacts with lipid membranes. Binding reaction and membrane location of CyA and analogs were examined with 2H-NMR, high-sensitivity isothermal titration calorimetry (ITC), and CD spectroscopy. Effects of CyA and charged analogs on the phosphocholine head group and on the membrane interior were investigated using selectively deuterated phospholipids. Incorporation of cyclosporin generated small disordering of the lipid acyl chains. Binding of CyA and neutral and positively charged analogs to lipid membranes showed endothermic heats of reaction between + 5.9 and + 11.3 kcal/mol, whereas enthalpy of binding was close to zero for the negatively charged derivative. Binding constants of cyclosporines to liposomal membranes were in the range of K(P) = 1650-5560 M(- 1) depending on the cholesterol content. (2)H-NMR provides evidence that CyA is essentially located in the interior of the bilayer membrane. For the charged analogs an additional interaction occurs at the head group level, placing the polar groups of these CyA analogs in the vicinity of the phosphocholine dipoles. The association of CyA and its analogs is accompanied by a positive enthalpy change, which is overcompensated by positive entropy changes. Binding of CyA to lipid membranes thus follows the classical hydrophobic effect, which is in contrast to many other peptide-lipid binding reactions.
authors.affiliation: Department of Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schote
authors.forename: Peter
authors.initials: P
authors.lastname: Ganz
authors.forename: Alfred
authors.initials: A
authors.lastname: Fahr
authors.forename: Joachim
authors.initials: J
authors.lastname: Seelig
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D002151:Calorimetry; D002942:Circular Dichroism; D003524:Cyclosporins / Q000737:chemistry*; D003903:Deuterium; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D010713:Phosphatidylcholines / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012995:Solubility; D013816:Thermodynamics; D014466:Ultraviolet Rays
chemical_list: D000596:Amino Acids; D003524:Cyclosporins; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D012710:Serum Albumin, Bovine; D003903:Deuterium; C028694:1-palmitoyl-2-oleoylphosphatidylcholine