The coupling characteristics and the proton transfer mechanisms of guanine–Na + monohydrate are determined in this investigation after the implementation of the geometry optimization and the harmonic vibrational frequency calculations. There are two elementary coupling modes: the interaction of monohydrated sodium ion with two heteroatoms which form a ringed coupling, and hydrogen-bond involved coupling mode. Two potential reaction pathways, coupling mode and hydration have been taken into account, and the accurate values of binding energy are corrected for basis set superposition error (BSSE) and zero-point vibrational energy (ZPVE). Relative energies of the hydrated guanine–sodium ion complexes indicate that the ringed-coupling complexes are predominant geometries with much lower energies. Monohydrated sodium ion coupling with O6 and N7 generates the most stable geometry with a five-member cycle. Sodium ion plays an important role in the tautomerization for guanine–sodium ion complexes. This investigation indicates that the stable cation-π complexes cannot be optimized for guanine–sodium ion monohydrate. Amino-involved coupling often gives rise to a twisted four-membered cycle with unrealistic distribution of positive charge and higher energies. The rotation of amino group is likely to lead to the redistribution of the base pair hydration bonding. Effective distribution of the positive charge is an important factor in the stabilization of biological systems and binding energies for the monohydrated guanine–sodium ion complexes. The enolic coupling complex has the higher energy than the keto type due to the hindrance for the positive charge.