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 (Ln³⁺) have a role in biology. Two types of MDH exist in methane-utilizing bacteria: one that is Ca²⁺-dependent (MxaF) and another that is Ln³⁺-dependent. Given that the triply charged Ln³⁺ are strongly hydrated, it is not clear how preference for Ln³⁺ is manifested and if the Ca²⁺-dependent MxaF protein can also bind Ln³⁺ ions. A computational approach was used to estimate the Gibbs energy differences between the binding of Ln³⁺ and Ca²⁺ to MDH using density functional theory. The results show that both proteins bind La³⁺ with higher affinity than Ca²⁺, albeit with a more pronounced difference in the case of Ln³⁺-dependent MDH. Interestingly, the binding of heavier lanthanides is preferred over the binding of La³⁺, with Gd³⁺ showing the highest affinity for both proteins of all Ln³⁺ ions that were tested (La³⁺, Sm³⁺, Gd³⁺, Dy³⁺, and Lu³⁺). Energy decomposition analysis reveals that the higher affinity of La³⁺ than Ca²⁺ to MDH is due to stronger contributions of electrostatics and polarization, which overcome the high cost of desolvating the ion.