Models of oximes RS-170B, HI-6 and RS-169A were prepared with Insight II (Accelrys, San Diego) as described earlier for HI-6 and similar imidazole oximes.17 (link),18 (link) The crystal structure of soman-TcAChE conjugate (PDB id 2WFZ) was used as a source of phosphonylated active center serine, and was pasted into 3D structure of human AChE (PDB id 4EY4). All water molecules and reversibly bound ligands were removed, while incompletely resolved amino acid side-chains were repaired. Oximes were oriented into the soman-hAChE gorge with their oximate oxygens approx. 4 Å from the conjugated phosphorus atom. A flexible distance constraint was placed between those two atoms at 3 Å, and molecular dynamics (MD) calculations were performed as described before.18 (link) Only selected hAChE side-chains (Y70, Y124, S203, W286, F295, F297, Y341 and H447) and the phosphonyl conjugate were allowed to rotate during simulation together with oxime. Ten calculations were performed per oxime. Resulting structures were visualized using Discovery Studio Visualizer 4.0 (Accelrys, San Diego).
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Modeling Oxime Interactions with Phosphonylated AChE
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Other organizations : Institute for Medical Research and Occupational Health, Scripps Research Institute, University of Montana, University of Hradec Králové
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Variable analysis
independent variables
- Orientation of oximes (RS-170B, HI-6, and RS-169A) into the soman-hAChE gorge
- Resulting structures of the oxime-hAChE complexes
- Crystal structure of soman-TcAChE conjugate (PDB id 2WFZ) used as a source of phosphonylated active center serine
- Water molecules and reversibly bound ligands removed
- Incompletely resolved amino acid side-chains repaired
- Oxime oximate oxygens positioned approximately 4 Å from the conjugated phosphorus atom
- Flexible distance constraint of 3 Å between the oximate oxygen and conjugated phosphorus atom
- Only selected hAChE side-chains (Y70, Y124, S203, W286, F295, F297, Y341 and H447) and the phosphonyl conjugate allowed to rotate during simulation together with oxime
- Ten calculations performed per oxime
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