A simple but effective modeling strategy for structural properties of non‐heme Fe(II) sites in proteins: Test of force field models and application to proteins in the AlkB family

To facilitate computational study of proteins in the AlkB family and related α-ketoglutarate/Fe(II)-dependent dioxygenases, we have tested a simple modeling strategy for the non-heme Fe(II) site in which the iron is represented by a simple +2 point charge with Lennard-Jones parameters. Calculations for an AlkB active site model in the gas phase and ∼150 ns molecular dynamics (MD) simulations for two enzyme-dsDNA complexes (E. coli AlkB-dsDNA and ABH2-dsDNA) suggest that this simple modeling strategy provides a satisfactory description of structural properties of the Fe(II) site in AlkB enzymes, provided that care is exercised to control the binding mode of carboxylate (Asp) to the iron. MD simulations using the model for AlkB-dsDNA and ABH2-dsDNA systems find that although the structural features for the latter are overall in good agreement with the crystal structure, the dsDNA, and AlkB-dsDNA interface undergo substantial changes during the MD simulations from the crystal structure. Even for ABH2, new interactions form between a long loop region and dsDNA upon structural relaxation of the loop, supporting the role of this loop in DNA binding despite the lack of interactions between them in the crystal structure. Analysis of DNA backbone torsional distributions helps identify regions that adopt strained conformations. Collectively, the results highlight that crystal packing may have a significant impact on the structure of protein-DNA complexes; the simulations also provide additional insights regarding why AlkB and ABH2 prefer single-strand and double-strand DNA, respectively, as substrate.