A physical interpretation of the Topal-Fresco [Nature 263, 285 (1976)] model for spontaneous base substitutions suggests that hydrogen-bonded DNA protons satisfy the criteria for a classical noninteracting isolated system. Accessible states for duplex G-C protons include the keto-amino state and the sir complementary enol-imine isomers. Hydrogen-bonded enol and imine protons occupy symmetric double-minima created by the two sets of indistinguishable electron lone pairs and a single proton belonging to each enol-imine end group. These protons will consequently participate in coupled quantum mechanical flip-flop, tunneling back and forth between symmetric energy wells. This results in a quantum mixing of proton energy states where the lowest energy stare will be a linear combination of available G-C isomers. The resulting conclusion is that metastable keto-amino G-C protons will populate accessible enol-imine stationary states at rates governed by quantum laws of statistical equilibrium consistent with achieving the lowest energy condition for duplex G-C protons. Enol-imine G-C stationary states are bound more tightly, of the order of 3 to 12 kcal/mol, which requires a modified mode of Topal-Fresco replication that will inhibit reequilibration of enol and imine G and C template isomers and, thus, promote the formation of complementary mispairs. The model is demonstrated on time-dependent base substitutions expressed by T4 phage DNA systems where data are consistent with model explanations, including the prediction that time-dependent evolutionary transversion sites will exhibit both G-C-to-T-A and G-C-to-C-G transversions at replication, due to proton flip-flop alteration of G template genetic specificity. The observation that A-T sites are resistant to time-dependent evolutionary base substitutions, expressed exclusively at G-C sites, allows codons to be classified as either evolutionary sensitive (16 codons) or evolutionary resistant (8 codons). These criteria provide possible explanations for expansion properties of the CGG fragile X sequences. Enol-imine G-C stationary states appear to have been
