insights into the dimer structure and deiodinase activity of type III iodothyronine deiodinase from bioinformatics, molecular dynamics simulations, and QM/MM calculations.

The homodimeric family of iodothyronine deiodinases (Dios) regioselectively remove iodine from thyroid hormones. Currently, structural data has only been reported for the monomer of the type III thioredoxin (Trx) fold catalytic domain (Dio3), but the mode of dimerization has not yet been determined. Various groups have proposed dimer structures that are similar to the A-type and B-type dimerization modes of peroxiredoxins. Computational methods are used to compare the sequence of Dio3 to related proteins known to form A-type and B-type dimers. Sequence analysis and protein-protein docking methods suggest that Dio3 is more consistent with proteins that adopt B-type dimerization. Molecular dynamics (MD) simulations of the refined Dio3 dimer constructed using the SymmDock and GalaxyRefineComplex databases indicate stable dimer formation along the βα interface consistent with other Trx fold B-type dimers. Free energy calculations show that the dimer is stabilized by interdimer interactions between the β-sheets and α-helices. A comparison of MD simulations of the and thyroxine-bound dimers suggests that the active site binding pocket is not affected by dimerization. Determination of the transition state for deiodination of thyroxine from the monomer structure using QM/MM methods provides an activation barrier consistent with previous small model DFT studies.Communicated by Ramaswamy H. Sarma.