Modeling and Inhibitor Design of Ca(2+)-Independent Phospholipase A2

Ca(2+)-independent phospholipase A2 (iPLA2) is a water-soluble enzyme that is active in association with lipid membranes. The deregulation of iPLA2 causes uncontrolled inflammation that plays a role in a large number of diseases. The design of selective inhibitors of iPLA2 has been complicated by the absence of any X-ray or NMR information about the enzyme structure. Here we have carried out microsecond MD simulations on homology models of iPLA2 to reach a complete understanding of the dynamic and membrane-related processes associated with the enzyme function and inhibition. The simulations help answer questions that have challenged scientists in this field for decades about the nature of the protein-bilayers complex, the importance of dynamics in the regulation of the active-site pocket, and the detailed mechanism of lipid extraction.View Large Image | View Hi-Res Image | Download PowerPoint Slide