Effect of the protein ligand in DMSO reductase studied by computational methods

The DMSO reductase family is the largest and most diverse family of mononuclear molybdenum oxygen-atom-transfer proteins. Their active sites contain a Mo ion coordinated to two molybdopterin ligands, one oxo group in the oxidised state, and one additional, often protein-derived ligand. We have used density-functional theory to evaluate how the fourth ligand (serine, cysteine, selenocysteine, OH^-, O^2-, SH^-, or S^2-) affects the geometries, reaction mechanism, reaction energies, and reduction potentials of intermediates in the DMSO reductase reaction. Our results show that there are only small changes in the geometries of the reactant and product states, except from the elongation of the MoX bond as the ionic radius of XO, S, Se increases. The five ligands with a single negative charge gave an identical two-step reaction mechanism, in which DMSO first binds to the reduced active site, after which the SO bond is cleaved, concomitantly with the transfer of two electrons from Mo in a rate-determining second transition state. The five models gave similar activation energies of 69-85kJ/mol, with SH^- giving the lowest barrier. In contrast, the O^2- and S^2- ligands gave much higher activation energies (212 and 168kJ/mol) and differing mechanisms (a more symmetric intermediate for O^2- and a one-step reaction without any intermediate for S^2-). The high activation energies are caused by a less exothermic reaction energy, 13-25kJ/mol, and by a more stable reactant state owing to the strong MoO^2- or MoS^2- bonds.