Oxyanion selectivity in sulfate and molybdate transport proteins: an ab initio/CDM study

A striking feature of sulfate (SO(4)(2-)) and molybdate (MoO(4)(2-)) transport proteins, such as SBP and ModA, which specifically bind SO(4)(2-) and MoO(4)(2-), respectively, is their ability to discriminate very similar anions with the same net charge, geometry, and hydrogen-bonding properties. Here, we determine to what extent (1) oxyanion-solvent interactions, (2) oxyanion-amino acid interactions, and (3) the anion-binding pocket sizes of the cognate protein contribute to the anion selectivity process in SO(4)(2-) and MoO(4)(2-) transport proteins by computing the free energies for replacing SO(4)(2-) with MoO(4)(2)(-)/WO(4)(2-) in model SO(4)(2-)-binding sites of varying degrees of solvent exposure using a combined quantum mechanical/continuum dielectric approach. The calculations reveal that MoO(4)(2-) transport proteins, such as ModA, specifically bind MoO(4)(2-)/WO(4)(2-) but not SO(4)(2-), mainly because the desolvation penalty of MoO(4)(2-)/WO(4)(2-) is significantly less than that of SO(4)(2-) and, to a lesser extent, because the large and rigid cavity in these proteins attenuates ligand interactions with SO(4)(2-), as compared to MoO(4)(2-). On the other hand, SO(4)(2-) transport proteins prefer SO(4)(2-) to MoO(4)(2-)/WO(4)(2-) because the small anion-binding pocket characteristic of these proteins inhibits binding of the larger MoO(4)(2-) and WO(4)(2-) anions. The calculations also help to explain the absence of positively charged Lys/Arg side chains in the anion-binding sites of SBP and ModA. During evolution, these transport proteins may have excluded cationic ligands from their binding sites because, on one hand, Lys/Arg do not contribute to the selectivity of the binding pocket and, on the other, they substantially stabilize the complex between the oxyanion and protein ligands, which in turn would prohibit the rapid release of the bound oxyanion at a certain stage during the transport process.