SELECTIN-LIGAND INTERACTIONS REVEALED BY MOLECULAR-DYNAMICS SIMULATION IN SOLUTION

Through a computer modeling and simulation technique, we investigated the binding mode of a complex of E-selectin-GSC-150, which is a novel selectin blocker. GSC-150 is the S'-sulfated Lewis X derivative with a long, branched alkyl chain. Initial attempts to construct a model for E-selectin-GSC-150 complex were performed based on a previously repor ted model of E-selectin-sialyl Lewis X (sLe(x)) complex [Kogan, T. P.; Revelle, B. M.; Tapp, S.; Scott, D.; Beek, P. J. J. Biol. Chem. 1995, 270, 14047-14055]. In our model, the carbohydrate portion of GSC-150 interacted with the protein in a similar manner as that of sLe(x) repo rted previously. Interestingly, each of the branched alkyl chains exte nded on the surface of E-selectin and interacted with two different hy drophobic portions. One of these hydrophobic portions consists of Tyr4 4, Pro46, and Tyr48. Another portion forms a shallow cavity, and it co nsists of Ala9, Leu114, and the alkyl moieties of the side chains of L ys111, Lys112, and Lys113. A subsequent 200-ps molecular dynamics simu lation in solution revealed that the interactions involved in the suga r portion of the ligand were relatively weak, whereas the hydrophobic interactions involved in the branched alkyl chains were fairly stable in solution. These results suggest that the branched alkyl chain serve s as an ''anchor'' for the tight binding of GSC-150 on the surface of E-Selectin. This is the first attempt to evaluate the dynamics of E-Se lectin-ligand interactions in solution, and it sheds light on the natu re of ligand recognition by selectins.