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

[Image: see text] 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(3+)) have a role in biology. Two types of MDH exist in methane-utilizing bacteria: one that is Ca(2+)-dependent (MxaF) and another that is Ln(3+)-dependent. Given that the triply charged Ln(3+) are strongly hydrated, it is not clear how preference for Ln(3+) is manifested and if the Ca(2+)-dependent MxaF protein can also bind Ln(3+) ions. A computational approach was used to estimate the Gibbs energy differences between the binding of Ln(3+) and Ca(2+) to MDH using density functional theory. The results show that both proteins bind La(3+) with higher affinity than Ca(2+), albeit with a more pronounced difference in the case of Ln(3+)-dependent MDH. Interestingly, the binding of heavier lanthanides is preferred over the binding of La(3+), with Gd(3+) showing the highest affinity for both proteins of all Ln(3+) ions that were tested (La(3+), Sm(3+), Gd(3+), Dy(3+), and Lu(3+)). Energy decomposition analysis reveals that the higher affinity of La(3+) than Ca(2+) to MDH is due to stronger contributions of electrostatics and polarization, which overcome the high cost of desolvating the ion.