Optimization of Interstrand Hydrophobic Packing Interactions within Unnatural DNA Base Pairs

Matsuda, Shigeo; Romesberg, Floyd E.

doi:10.1021/ja047291m

Cited by 64 publications

(49 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…8,9,11,14,15,20,22,[28][29][30][31][32][33][34] From these, 60 were collected ( Figure 2) and their phosphoramidites incorporated into the 3' end of a 24-mer primer oligonucleotide and at the 24 th position of a complementary 45-mer template oligonucleotide. Hybridization of any given primer strand with any template strand results in an unnatural primer terminus (dX:dY, where dX is the primer nucleobase and dY is the template nucleobase).…”

Section: Screening For Unnatural Base Pairsmentioning

confidence: 99%

“…Indeed, several nucleotides bearing predominantly hydrophobic nucleobase analogs have been shown to pair stably and selectively in duplex DNA. 13,14 We, 9,10,15,16 and others, 8,12,[17][18][19] have shown that hydrophobic forces are also sufficient for the enzymatic synthesis of an unnatural base pair by incorporation of an unnatural nucleoside triphosphate against a template unnatural nucleotide; however, synthesis beyond the unnatural base pair, i.e. extension, tends to be relatively inefficient and generally limits the utility of these base pairs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery, Characterization, and Optimization of an Unnatural Base Pair for Expansion of the Genetic Alphabet

et al. 2008

Self Cite

View full text Add to dashboard Cite

DNA is inherently limited by its four natural nucleotides. Efforts to expand the genetic alphabet, by addition of an unnatural base pair, promise to expand the biotechnological applications available for DNA as well as being an essential first step towards expansion of the genetic code. We have conducted two independent screens of hydrophobic unnatural nucleotides to identify novel candidate base pairs that are well recognized by a natural DNA polymerase. From a pool of 3600 candidate base pairs, both screens identified the same base pair, dSICS:dMMO2, which we report here. Using a series of related analogs, we performed a detailed structure-activity relationship analysis, which allowed us to identify the essential functional groups on each nucleobase. From the results of these studies, we designed an optimized base pair, d5SICS:dMMO2, which is efficiently and selectively synthesized by Kf within the context of natural DNA.

show abstract

Section: Screening For Unnatural Base Pairsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery, Characterization, and Optimization of an Unnatural Base Pair for Expansion of the Genetic Alphabet

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…This may also hold true for the MMAN self-pair with only 4-position methyl groups, which is more stable than the MAN self-pair, which has no methyl groups at the 4-position, and the DMMAN self-pair, which has an additional 5-position methyl group. The stability of the unnatural self-pairs of MAN, MMAN, and DMMAN was lower than that of AM, ADM, and even simple benzene (T m = 52.8 o C) 10 self-pairs. This result indicates that the methylation at the ortho-amine probably disrupts the optimized packing of the 2-position amine group in the interbase interface and hence significantly destabilized the self-pairs.…”

Section: Scheme 1 Synthesis Of Aminobenzene Derivatized Nucleotidesmentioning

confidence: 81%

2-Aminobenzene Derivatives as Unnatural Nucleobases and Their DNA Duplex Stabilities

Heo¹,

Hwang

2010

Bulletin of the Korean Chemical Society

View full text Add to dashboard Cite

Scheme 1. Synthesis of aminobenzene derivatized nucleotidesThe thermal stability and faithful replication of a natural DNA duplex is based on the Watson-Crick hydrogen-bonding (H-bonding) patterns of dA:dT and dC:dG base pairs. Additional stable and selective unnatural base pairs would facilitate hybridization and encoding experiments in cases where natural sequences cross hybridize or where increased information storage is desirable.1 Recent studies have shown that H-bonds between unnatural nucleobases are not absolutely essential for selective base pairing.2 On the basis of this concept, a large number of nucleotides bearing large and predominantly hydrophobic nucleobases have been synthesized and characterized according to the isocarbostyril, napthyl, and indole scaffolds, whose pairing is mediated by hydrophobic interactions.2 From these studies, several self-pairs (formed by pairing of identical analogues) and heteropairs (formed by pairing of 2 different analogues) that rival natural base pairs in terms of thermal stability and selectivity against mispairing have been identified. A larger aromatic surface area increases the thermal stability and selectivity of unnatural base pairs, and a structural study suggested that analogues intercalate into the opposite strand between the pairing nucleobase and an adjacent nucleobase. 3 We therefore became interested in examining nucleobase analogues that lack a large aromatic surface area but are optimized to interact edgeon analogous to natural Watson-Crick base pairing.Recent works have focused on the systematic examination of the contribution to base pair stability of nucleobase shape, hydrophobicity, dipole moment, and polarizability within the benzene, pyridine, or pyridone scaffolds. 4 Our current focus is identifying combinations of methyl-group substitutions at the major groove position and heteroatom derivatizations at the ortho-position in the unnatural nucleobase scaffold responsible for the improved stability of these smaller unnatural nucleobases. Although 2-aminophenyl derivatives are good candidates as hydrophobic surrogates, relatively little work has been done on their deoxy-C-nucleosides. Some research groups have synthesized these derivatives by inducing a titanium aldol reaction/ O-H insertion reaction between diazoketone and aminobenzaldehyde 5 and C-C bond formation between aminophenyl derivative and 2'-deoxy-D-ribono-lactone. 6 However, these processes have the disadvantages of long steps and low stereoselectivity. Further, no previous study has examined the effect of 2-aminophenyl derivatives on the thermal stability of the DNA duplex. To further understand how 2-aminobenzene derivatives contribute to DNA stability, we synthesized and characterized the 2-aminobenzene nucleotide analogues AM and ADM (Figure 1, Scheme 1). We also synthesized the N-methylated aminobenzene derivatives MAN, MMAN, and DMMAN to evaluate the amino functional group at the 2-position for its role in optimizing DNA stability. A palladium-mediated Heck-type coupling reac...

show abstract

“…Romesberg, Schultz, and coworkers have synthesized a number of analogues such as 7-azaindole (7-AI), propynylisocarbostyrile (PICS) (Fig. 13-5) as well as some fluoroaromatic analogues [68] and evaluated them as potential self-pairing nucleosides [69,70]. Various of the analogues prepared are also recognized with reasonable selectivity by DNA polymerases [49,68,71].…”

Section: Altered Basesmentioning

confidence: 99%

Self‐Replication in Chemistry and Biology

Holliger

Loakes

2009

Systems Biology and Synthetic Biology

View full text Add to dashboard Cite

Optimization of Interstrand Hydrophobic Packing Interactions within Unnatural DNA Base Pairs

Cited by 64 publications

References 46 publications

Discovery, Characterization, and Optimization of an Unnatural Base Pair for Expansion of the Genetic Alphabet

Discovery, Characterization, and Optimization of an Unnatural Base Pair for Expansion of the Genetic Alphabet

2-Aminobenzene Derivatives as Unnatural Nucleobases and Their DNA Duplex Stabilities

Self‐Replication in Chemistry and Biology

Contact Info

Product

Resources

About