Molecular Simulation Of The Interaction Mechanism Of Helminth's Complex ? And Its Inhibitors

Many different kinds of diseases are caused by helminth,which are widely spread all over the world. Helminth's complex I is closely related to electron transfer and energy metabolism of helminth. It is the entrance of electron transfer chain for NADH or FADH2. The proton pump formed during the electron transfer acting as the driving force for the synthesis of ATP. Therefore, the inhibition of complex I can interrupt the energy production of helminth, and eventually lead to the death of helminth. Apparently, helminth complex I becomes a potential target for the drug against helminthiasis. However, there are few research on the interaction between complex I and its inhibitors because of the huge and multi-subunits structure of complex I. Up to now, complex I from Thermus thermophiles is the only one whose amino acid sequence and 3D structure have been determined through experimental method. Caenorhabditis elegans is the model organism of helminth. In this paper, the interaction mechanism of the binding modes of complex I (from T. thermophiles and C. elegans) with two substrates (ubiquinone and rhodoquinone) and three similar inhibitors (Ukulactone A, Ukulactone B and Wortmannilactone F) was studied through homologous modeling, molecular docking and molecular dynamics simulation. In addition, the key amino acid residues were identified and the type of these residues were elucidated. The result obtained here will be benefit to the development and modification of the drugs against helminthiasis. The contents are described as follows.(1) Using Nqo4 and Nqo6 subunits in the active pocket of T. thermophiles complex I as the template, homology modeling was applied to construct the C. elegans complex I whose activity pocket model formed by CI-49KD and PSST subunits. The result showed that this model was low-energy and structurally stable, so it can be used as the receptor for molecular simulation.(2) The initial docking poses of the two receptors (the active pockets of T. thermophiles complex I and C. elegans complex I) and five ligands (two substrates and three representative inhibitors Ukulactone A, Ukulactone B and Wortmannilactone F) were obtained through molecular docking. When C. elegans complex I combined with three inhibitors, there were two kinds of docking modes. One was the 5,6-dihydro-2H-pyran interact with CI-49KD, in the meantime, the 2-oxabicyclo[2,2,1]heptane-3,5-dione interact with PSST, and the other was opposite. The binding free energy of these complexes indicated that both of the docking models could be the final docking poses of C. elegans complex I and three kinds of inhibitors.(3) According to the binding free energy and three-dimensional structure of the receptor-ligand complex, it was concluded that since isoprenoid chain in the substrates was much longer than that in the inhibitors, the substrates can interact with more amino acid residues in the receptors. As a result, the binding free energies for the substrates were stronger than those of inhibitors. Met412 in T. thermophiles is equivalent to Met455 in C. elegans. Thr101 and Met412/Met455 often had a great contribution to the combination of receptors and ligands. In most cases,1 or 2 amino acid residues in Nqo4/CI-49KD can form bonds with the cyclic structure of the ligands, resulting in an increased stability of the binding pose.