Constructing a molecular model of the interaction between Antithrombin-III and a potent synthetic heparin Analogue.

Abstract: Information about the antithrombin 111-heparin interaction is deduced from the following: (i) structure-activity studies of various synthetic analogues of the antithrombin I11 binding pentasaccharide domain of heparin, which revealed that essential sulfate and carboxylate substituents are located at opposite sides of the pentasaccharide molecule; (ii) studies that designated the heparin-binding amino acid residues of antithrombin 111; (iii) a molecular model of antithrombin 111, constructed on the basis of the crystal structure of a1-antitrypsin. From these studies it could be deduced that both the protein and the carbohydrate display an asymmetric assembly of essential interaction points. Docking trials indicated a single complex in which the interaction points are complementary. The latter complex was optimized by molecular dynamics simulations. The final model reveals, for the first time, how a well-defined region of a sulfated polysaccharide can interact specifically with a complementary binding site on a functional protein.