Understanding the binding mode and function of glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum with TLR2 complexes

The parasitic protozoa, Plasmodium falciparum, P. vivax, P. malariae, and P. ovale, cause malaria in humans. Of these, the GPIs of Plasmodium falciparum are thought to be an important factor in the induction of proinflammatory responses. The GPIs of Plasmodium falciparum induces host cellular responses mainly through TLR2/MyD88-mediated signaling. However, the detailed molecular properties of GPIs Plasmodium falciparum interacting with the TLR2 that induces heterodimerization with TLR1 or TLR6 are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. To enable first predictions of the receptor-ligand interaction sites, docking combined with molecular dynamics simulation has been employed to understand the binding mode of GPIs of Plasmodium falciparum derivatives to TLR2 pathways. We have taken the crystal co-ordinates of TLR1/2 and TLR2/6 complexes and subsequently tested with the GPIs of Plasmodium falciparum and their derivatives. Our studies have shown that the lipopeptides binding pocket of TLR2 can accommodate three fatty acid substituents of GPIs of Plasmodium falciparum and thereby activate the TLR2/1 complex, whereas their derivatives, sn-2 lyso GPIs, that contain two fatty acid substituents accommodated by TLR2/6. The current predicted complexes are analogous to the crystal structure of TLR2/1-tri-acyl lipopeptides and TLR2/6-di-acylated lipopeptides, respectively. Our data suggests that the lipid portions of the GPIs of Plasmodium falciparum ligands play crucial role in determining their TLR recognition specificity. The modes of action of GPIs binding site residues are consistent with previous biochemical/mutagenesis studies.