Redesigning the Architecture of the Base Pair: Toward Biochemical and Biological Function of New Genetic Sets

Abstract

Recognition of the nucleic acid bases within the DNA scaffold comprises the basis for transmission of genetic information, dictating protein and cell assembly, organismal development, and evolution. Driven in part by the need to test our current understanding of this information transfer, chemists have begun to design and synthesize nonnatural bases and base pair structures to mimic the function of DNA without relying on Nature’s purine-pyrimidine base pair scaffold. Multiple examples have been recently described of new genetic architectures that self-assemble stably and sequence specifically in vitro, and experiments with polymerases in vitro show that at least isolated unnatural base pairs can be replicated as well. Moreover, recent experiments with unnatural bases in bacterial cells have demonstrated surprisingly efficient reading of the chemical information. This suggests the future possibility of redesigning and replacing the chemical information of an evolving cell while retaining biological function. Such unnatural base pair components, whether recognized by nature or not, are already proving useful in biotechnology. In addition to practical applications, this chemical approach also gives basic insight into the forces and mechanisms that govern DNA structure and replication.

Cooperative Hybridization of Oligonucleotides

“…Integration of the cooperative hybridization mechanism with functional nucleic acids such as aptamers 53 and ribozymes, 54 expanded nucleic acid alphabets, 55 DNAdirected chemical synthesis, 56 or other nanomaterials 57 can broaden the set of chemistries that can serve as both input and output of an engineered nucleic acid system.…”

Metal–base pairing in DNA

“…Among these artificial nucleobases, some were developed for studying the hydrogen bonding and stacking forces that hold together the double helix [13]. Others were incorporated into DNA to create a new set of base pairs with pairing abilities orthogonal to the natural Watson-Crick base pairs [14]. Again other artificial bases were developed for the analytical recognition of single nucleotide polymorphisms (SNPs) [15].…”

Site-Specific Incorporation of Functional Components into RNA by an Unnatural Base Pair Transcription System

“…The realization of this genetic expansion system requires the development of an unnatural base pair that functions in biological systems, such as replication, transcription, and translation, with highly exclusive selectivity as a third base pair, along with the natural A-T and G-C pairs. Researchers are attempting to create expanded systems, and many unnatural base pairs have been designed and tested in in vitro biological systems [1][2][3][4][5]. Among them, some unnatural base pairs have exhibited high selectivity as a third base pair in PCR amplification and/or transcription [6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”