High-Fidelity Sequence-Selective Duplex Formation by Recognition-Encoded Melamine Oligomers

Trošelj, Pavle; Bolgar, Peter; Ballester, Pablo; Hunter, Christopher A.

doi:10.1021/jacs.1c02275

Cited by 24 publications

(25 citation statements)

References 56 publications

(93 reference statements)

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“…The values of EM and K ·EM calculated using eq are reported in Table . The value of EM (20–30 mM) is similar to the values we have reported previously for a number of different H-bonded duplex architectures. − The product K ·EM measures the chelate cooperativity associated with duplex formation, and the value is significantly greater than one for this system, which is indicative of a fully assembled duplex.…”

Section: Resultssupporting

confidence: 83%

“…Figure shows a noncovalent analogue of the covalent duplex formed in the template-directed replication cycle illustrated in Figure . The phenol·phosphine oxide base-pair is similar in geometry to the ester base-pair, and we have established previously that the H-bond used in this base-pairing interaction is sufficiently stable to support duplex formation in nonpolar solvents. − In this paper, we describe the synthesis of a new family of phenol and phosphine oxide triazole oligomers, demonstrate duplex formation via H-bonding interactions, and show that a covalent base-pair can be used as a primer to direct H-bond template-directed oligomer synthesis.…”

Section: Introductionmentioning

confidence: 78%

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H-Bond Templated Oligomer Synthesis Using a Covalent Primer

Núñez‐Villanueva

Hunter

2022

J. Am. Chem. Soc.

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Template-directed synthesis of nucleic acids in the polymerase chain reaction is based on the use of a primer, which is elongated in the replication process. The attachment of a high affinity primer to the end of a template chain has been implemented for templating the synthesis of triazole oligomers. A covalent ester base-pair was used to attach a primer to a mixed sequence template. The resulting primed template has phenol recognition units on the template, which can form noncovalent base-pairs with phosphine oxide monomers via H-bonding, and an alkyne group on the primer, which can react with the azide group on a phosphine oxide monomer. Competition reactions between azides bearing phosphine oxide and phenol recognition groups were used to demonstrate a substantial template effect, due to H-bonding interactions between the phenols on the template and phosphine oxides on the azide. The largest rate acceleration was observed when a phosphine oxide 2-mer was used, because this compound binds to the template with a higher affinity than compounds that can only make one H-bond. The 31 P NMR spectrum of the product duplex shows that the H-bonds responsible for the template effect are present in the product, and this result indicates that the covalent ester base-pairs and noncovalent H-bonded base-pairs developed here are geometrically compatible. Following the templated reaction, it is possible to regenerate the template and liberate the copy strand by hydrolysis of the ester base-pair used to attach the primer, thus completing a formal replication cycle.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 78%

H-Bond Templated Oligomer Synthesis Using a Covalent Primer

Núñez‐Villanueva

Hunter

2022

J. Am. Chem. Soc.

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“…Chem. Soc.202114386698678 H-Bond Self-Assembly: Folding versus Duplex FormationNúñez-VillanuevaD.IadevaiaG.StrossA.…”

Section: Key Referencesmentioning

confidence: 99%

“…Interactions between all pairwise combinations of 3-mer sequences have been measured for oligomers 3 and 10 . , The results are illustrated using a single base mismatch analysis in Figure . There are three sequence-complementary 3-mer duplexes, AAA · DDD , ADA · DAD , and AAD · ADD , and the first entry in each bar chart in Figure shows the association constant for formation of the duplex from the two complementary strands.…”

Section: Sequence-selectivity Of Duplex Formationmentioning

confidence: 99%

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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“…Compounding these challenges, the presence of the complementary recognition subunits required for templated polymerization means that genetic polymers will contain mutually reactive subunits with the potential to self-associate and fold in a multitude of ways. Despite these challenges, significant strides have been made in recent decades in the synthesis of polymers that mimic biomolecules: information storing sequence-defined polymers can now be made to considerable lengths, polymers that mimic the folding behavior of enzymes and ribozymes are built with ever-increasing sophistication, and many synthetic sequence-dependent duplex forming structures have been reported …”

Section: Introductionmentioning

confidence: 99%

Folding and Duplex Formation in Sequence-Defined Aniline Benzaldehyde Oligoarylacetylenes

Strom

Szostak

2022

J. Am. Chem. Soc.

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In all known genetic polymers, molecular recognition via hydrogen bonding between complementary subunits underpins their ability to encode and transmit information, to form sequence-defined duplexes, and to fold into catalytically active forms. Reversible covalent interactions between complementary subunits provide a different way to encode information, and potentially function, in sequence-defined oligomers. Here, we examine six oligoarylacetylene trimers composed of aniline and benzaldehyde subunits. Four of these trimers self-pair to form tworung duplex structures, and two form macrocyclic 1,3-folded structures. The equilibrium proportions of these structures can be driven to favor each of the observed structures almost entirely depending upon the concentration of trimers and an acid catalyst. Quenching the acidic trimer solutions with an organic base kinetically traps all species such that they can be isolated and characterized. Mixtures of complementary trimers form exclusively sequence-specific 3-rung duplexes. Our results suggest that reversible covalent bonds could in principle guide the formation of more complex folded conformations of longer oligomers.

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High-Fidelity Sequence-Selective Duplex Formation by Recognition-Encoded Melamine Oligomers

Cited by 24 publications

References 56 publications

H-Bond Templated Oligomer Synthesis Using a Covalent Primer

H-Bond Templated Oligomer Synthesis Using a Covalent Primer

Recognition-Encoded Synthetic Information Molecules

Folding and Duplex Formation in Sequence-Defined Aniline Benzaldehyde Oligoarylacetylenes

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