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 Ca2+-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 Ca2+-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 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 Ln(3+)-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 Ln(3+) 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.