Solvation reshapes the classical but not the quantum mechanism of double proton transfer in guanine-cytosine.

The tautomerization of the guanine-cytosine base pair via double proton transfer has been proposed as a source of spontaneous mutations in DNA. We construct a two-dimensional semiclassical framework based on B3LYP/def2-TZVP potential energy surfaces and a variational WKB approach to compare minimum energy paths and minimum action paths in gas-phase and solvated environments. In the gas phase, the two paths are nearly identical, with a concerted barrier of 0.691 eV and a metastable tautomer protected by a reverse barrier of 0.244 eV. In contrast, solvation reshapes the minimum energy path into a stepwise pathway, while the minimum action path remains concerted. This leads to a 70.3% enhancement in the forward tunneling transmission coefficient and order of magnitude differences in transmission probability at low energies. Despite this, forward rate constants differ only modestly due to compensation with the slightly higher minimum action path barrier. The near-vanishing reverse barrier in solution implies a tautomer lifetime of ∼0.3 ps, indicating rapid back-transfer. These results show that minimum energy pathways can misrepresent tunneling mechanisms in solvated environments and highlight the importance of multidimensional path optimization.