Rethinking nucleic acids from their origins to their applications

Benner, Steven A.

doi:10.1098/rstb.2022.0027

Cited by 19 publications

(11 citation statements)

References 109 publications

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“…Intermolecular polymerization ultimately leads to precipitation, and in Nature, the polyelectrolyte structure of nucleic acids helps to avoid this pathway. 24 The key parameter that governs the duplex channel is the product K EM d , where K is the association constant for formation of an intermolecular base-pair and EM d is the effective molarity for the intramolecular interactions that zip up the duplex. The channel leading to duplex assembly is downhill in free energy terms when K EM d > 1.…”

Section: Design Criteriamentioning

confidence: 99%

“…Figure shows that in addition to assembly of a duplex there are other possible outcomes of the formation of base-pairs in mixed sequence oligomers: intramolecular interactions lead to folding, and intermolecular interactions lead to polymeric networks. Intermolecular polymerization ultimately leads to precipitation, and in Nature, the polyelectrolyte structure of nucleic acids helps to avoid this pathway . The key parameter that governs the duplex channel is the product K EM d , where K is the association constant for formation of an intermolecular base-pair and EM d is the effective molarity for the intramolecular interactions that zip up the duplex.…”

Section: Design Criteriamentioning

confidence: 99%

“…These unrivalled properties have been exploited to develop programmable nanostructures and to discover new functional biopolymers using directed evolution. Analogues, where the furanose sugar, − the phosphate linker, − or the bases − have been replaced, also form sequence-selective duplexes, suggesting that it might be possible to develop different types of synthetic polymers that exhibit functional properties that are currently unique to nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

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Recognition-Encoded Synthetic Information Molecules

Iadevaia

Hunter

2023

Acc. Chem. Res.

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Conspectus Nucleic acids represent a unique class of highly programmable molecules, where the sequence of monomer units incorporated into the polymer chain can be read through duplex formation with a complementary oligomer. It should be possible to encode information in synthetic oligomers as a sequence of different monomer units in the same way that the four different bases program information into DNA and RNA. In this Account, we describe our efforts to develop synthetic duplex-forming oligomers composed of sequences of two complementary recognition units that can base-pair in organic solvents through formation of a single H-bond, and we outline some general guidelines for the design of new sequence-selective recognition systems. The design strategy has focused on three interchangeable modules that control recognition, synthesis, and backbone geometry. For a single H-bond to be effective as a base-pairing interaction, very polar recognition units, such as phosphine oxide and phenol, are required. Reliable base-pairing in organic solvents requires a nonpolar backbone, so that the only polar functional groups present are the donor and acceptor sites on the two recognition units. This criterion limits the range of functional groups that can be produced in the synthesis of oligomers. In addition, the chemistry used for polymerization should be orthogonal to the recognition units. Several compatible high yielding coupling chemistries that are suitable for the synthesis of recognition-encoded polymers are explored. Finally, the conformational properties of the backbone module play an important role in determining the supramolecular assembly pathways that are accessible to mixed sequence oligomers. Almost all complementary homo-oligomers will form duplexes provided the product of the association constant for formation of a base-pair and the effective molarity for the intramolecular base-pairing interactions that zip up the duplex is significantly greater than one. For these systems, the structure of the backbone does not play a major role, and the effective molarities for duplex formation tend to fall in the range 10–100 mM for both rigid and flexible backbones. For mixed sequences, intramolecular H-bonding interactions lead to folding. The competition between folding and duplex formation depends critically on the conformational properties of the backbone, and high-fidelity sequence-selective duplex formation is only observed for backbones that are sufficiently rigid to prevent short-range folding between bases that are close in sequence. The final section of the Account highlights the prospects for functional properties, other than duplex formation, that might be encoded with sequence.

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Section: Design Criteriamentioning

confidence: 99%

Section: Design Criteriamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recognition-Encoded Synthetic Information Molecules

Iadevaia

Hunter

2023

Acc. Chem. Res.

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“…These form orthogonal base pairs (A/T, G/C, P / Z , and B / S ) that follow both Watson–Crick pairing rules: hydrogen bonding and size complementarity (Figure A) . These meet the two structural requirements to support Darwinian evolution, a polyelectrolyte backbone and a size–shape regular building block that fits into an “aperiodic crystal.” H achimoji duplexes adopt the familiar A and B helical forms seen in standard DNA . Artificial genetic systems meeting these structural requirements can be used to evolve high-affinity aptamers, ,− enable highly multiplexed PCR, , and are used in commercial diagnostic kits testing for severe acute respiratory syndrome coronavirus 2, Middle East respiratory syndrome-coronavirus, dengue virus, murine norovirus, and others …”

Section: Introductionmentioning

confidence: 99%

Assessing Readability of an 8-Letter Expanded Deoxyribonucleic Acid Alphabet with Nanopores

et al. 2023

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Chemists have now synthesized new kinds of DNA that add nucleotides to the four standard nucleotides (guanine, adenine, cytosine, and thymine) found in standard Terran DNA. Such "artificially expanded genetic information systems" are today used in molecular diagnostics; to support directed evolution to create medically useful receptors, ligands, and catalysts; and to explore issues related to the early evolution of life. Further applications are limited by the inability to directly sequence DNA containing nonstandard nucleotides. Nanopore sequencing is wellsuited for this purpose, as it does not require enzymatic synthesis, amplification, or nucleotide modification. Here, we take the first steps to realize nanopore sequencing of an 8-letter "hachimoji" expanded DNA alphabet by assessing its nanopore signal range using the MspA (Mycobacterium smegmatis porin A) nanopore. We find that hachimoji DNA exhibits a broader signal range in nanopore sequencing than standard DNA alone and that hachimoji singlebase substitutions are distinguishable with high confidence. Because nanopore sequencing relies on a molecular motor to control the motion of DNA, we then assessed the compatibility of the Hel308 motor enzyme with nonstandard nucleotides by tracking the translocation of single Hel308 molecules along hachimoji DNA, monitoring the enzyme kinetics and premature enzyme dissociation from the DNA. We find that Hel308 is compatible with hachimoji DNA but dissociates more frequently when walking over Cglycoside nucleosides, compared to N-glycosides. C-glycocide nucleosides passing a particular site within Hel308 induce a higher likelihood of dissociation. This highlights the need to optimize nanopore sequencing motors to handle different glycosidic bonds. It may also inform designs of future alternative DNA systems that can be sequenced with existing motors and pores.

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“…[7][8][9][10][11][12][13][14][15][16] Proteins and nucleic acids both benefit from such an increase in chemodiversity. In the case of nucleic acids, the co-polymerization of modified nucleoside triphosphates enables Darwinian selection experiments to raise functional nucleic acids with enhanced properties, 8,[17][18][19] expand the genetic alphabet with orthogonal base pairs, 11,20,21 and functionally tag DNA and RNA. [22][23][24] Despite well-established protocols, most processes still rely on the stepwise incorporation of modified nucleotides by polymerases (Fig.…”

mentioning

confidence: 99%