Nucleic Acid Assembly Using Small Molecule Interactions

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Jain, Swapan Satyen
Hud, Nicholas V.
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Lifes origin is, in many ways, coupled to understanding the evolution of nucleic acids. In contemporary life, proteins and nucleic acids are intricately dependent upon each other for a host of functions including, but not limited to, replication and chemical ligation. Protein enzymes are necessary for the synthesis of DNA and RNA, while nucleic acids are necessary for both the coding and synthesis of proteins. According to the RNA World hypothesis, early life used nucleic acids for both information storage and chemical catalysis before the emergence of protein enzymes. However, it still remains a mystery how nucleic acids were able to assemble and replicate before the advent of protein enzymes. We have utilized the ability of small molecule intercalation to assemble nucleic acids into stable secondary structures. Our motivation in this pursuit comes from the recently proposed Molecular Midwife hypothesis where small molecules may have acted as nanoscale structural scaffolds upon which the nucleic acid bases were able to stack into stable structures and undergo assembly into polymers. We have also found that the kinetics and thermodynamics of small molecule-mediated assembly and secondary structure formation are strongly dependent upon oligonucleotide length. Small molecules bind to nucleic acids by multiple modes of binding and this phenomenon must be properly understood in order to achieve robust and versatile assembly of nucleic acid structures.
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