Preferential Binding of Lanthanides to Methanol Dehydrogenase Evaluated with Density Functional Theory.

Methanol dehydrogenase (MDH) is an enzyme used by certain bacteria for the oxidation of methanol to formaldehyde, which is a necessary metabolic reaction. The discovery of a lanthanide-dependent MDH reveals that lanthanide ions (Ln) have a role in biology. Two types of MDH exist in methane-utilizing bacteria: one that is Ca-dependent () and another that is Ln-dependent. Given that the triply charged Ln are strongly hydrated, it is not clear how preference for Ln is manifested and if the Ca-dependent protein can also bind Ln ions. A computational approach was used to estimate the Gibbs energy differences between the binding of Ln and Ca to MDH using density functional theory. The results show that both proteins bind La with higher affinity than Ca, albeit with a more pronounced difference in the case of Ln-dependent MDH. Interestingly, the binding of heavier lanthanides is preferred over the binding of La, with Gd showing the highest affinity for both proteins of all Ln ions that were tested (La, Sm, Gd, Dy, and Lu). Energy decomposition analysis reveals that the higher affinity of La than Ca to MDH is due to stronger contributions of electrostatics and polarization, which overcome the high cost of desolvating the ion.