Molecular dynamics simulation study on the interaction of KRN 7000 and three analogues with human CD1d

Many analogues of KRN 7000, a synthetic glycolipid (alpha-galactosylceramide) exhibiting immuno-stimulatory activity and antitumor properties, were previously synthesized and tested in order to understand the reasons for the resulting biological activity and Th1/Th2 cytokine profile. Principles have been established for the interaction of such glycolipids with the human CD1d molecule but the exact mechanism by which different ligands with the same polar head elicit distinct biological responses remains unclear. Based on these experiments and on the available crystal structures, protein-ligand interactions are explored using molecular dynamics simulations. Hydrogen bond interactions are examined with regard to the polar group orientation. The influence of modulations on the dynamic behavior of the CD1d-glycolipid complex is addressed. Overall, our data support the mechanism by which the shortening of the alpha-GalCer sphingosine chain causes a significant twist of the CD1d alpha 1 helix structure from residue Phe84 that affects the position of CD1d residues involved in the TCR recognition. (C) 2008 Elsevier Ltd. All rights reserved.