Accurate Base Pair Energies of Artificially Expanded Genetic Information Systems (AEGIS): Clues for Their Mutagenic...

Recently, several artificial nucleobases, such as B, S, J, V, X, K, P, and Z, have been proposed to help in the expansion of the genetic information system and diagnosis of diseases. Among these bases, P and Z were identified to form stable DNA and to participate in the replication. However, the stabilities of P:Z and other artificial base pairs are not fully understood. The abilities of these unnatural nucleobases in mispairing with themselves and with natural bases are also not known. Here, the ωB97X-D dispersion-corrected density functional theoretical and complete basis set (CBS-QB3) methods are used to obtain accurate structural and energetic data related to base pair interactions involving these unnatural nucleobases. The roles of protonation and deprotonation of certain artificial bases in inducing mutations are also studied. It is found that each artificial purine has a complementary artificial pyrimidine, the base pair interactions between which are similar to those of the natural Watson-Crick base pairs. Hence, these base pairs will function naturally and would not impart mutagenicity. Among these base pairs, the J:V complex is found to be the most stable and promising artificial base pair. Remarkably, the noncomplementary artificial nucleobases are found to form stable mispairs, which may generate mutagenic products in DNA. Similarly, the misinsertions of natural bases opposite artificial bases are also found to be mutagenic. The mechanisms of these mutations are explained in detail. These results are in agreement with earlier biochemical studies. It is thus expected that this study would aid in the advancement of the synthetic biology to design more robust artificial nucleotides.