DNA functionalization by dynamic chemistry

Area of Science:

• Chemical Biology
• Oligonucleotide Synthesis
• Dynamic Combinatorial Chemistry

Background:

• Dynamic combinatorial chemistry (DCC) offers an efficient route to molecular library generation through reversible reactions under thermodynamic control.
• DNA modification presents opportunities for novel functionalization and the creation of dynamic molecular systems.
• Acyclic diol linkers provide a versatile platform for modifying DNA oligonucleotides.

Purpose of the Study:

• To explore the chemical modification of DNA oligonucleotides using acyclic diol linkers.
• To demonstrate the potential of these modified DNA building blocks for generating libraries of reversibly interconverting molecules.
• To investigate the impact of these modifications on DNA base-pairing and mismatch formation.

Main Methods:

• Synthesis of phosphoramidite building blocks derived from D-threoninol with protected amino or thiol groups.
• Automated solid-phase synthesis for incorporating threoninol building blocks into 13mer oligonucleotides.
• Utilizing aldehyde-modified nucleobases and complementary DNA templates to study base-pairing equilibria and mismatch generation.

Main Results:

• Successful incorporation of threoninol phosphoramidite building blocks into DNA oligonucleotides.
• Generation of a significant fraction of all possible base-pair mismatches.
• Achieved over 80% selectivity for guanine aldehyde templated by cytosine-containing DNA.

Conclusions:

• Acyclic diol linkers can functionalize DNA and create dynamic, interconverting building blocks.
• The modified DNA backbone exhibits increased plasticity, leading to an elevated occurrence of base-pair mismatches.
• This approach demonstrates high selectivity for specific base-pair templating, particularly guanine-cytosine.