Self-assembly of nucleobase analogs in water: supramolecular polymers, controllable materials and models for proto-nucleic acid
Cafferty, Brian Joseph
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Reversible self-assembly in water of small molecules into ordered structures is an essential process that underlies many biological functions and developmental strategies for environmentally responsive and biocompatible materials. However, a thorough understanding of the physicochemical principles that govern assembly of low molecular weight molecules in water is largely lacking. In this thesis, I describe the development and characterization of water-based self-assembly systems that utilize hexameric ‘rosette’ motifs and form supramolecular polymers and hydrogels. Mimicking the base pairing interactions of nucleic acids, hydrogen bonding directs assembly of monomers (containing either triaminopyrimidine and cyanuric acid, or melamine and barbituric acid recognition elements) into bimolecular rosettes that stack into micron-length supramolecular polymers. The hydrophobic effect drives the assembly of the small water-soluble monomers and is responsible for the observed cooperative assembly mechanism. For one system, monomer assembly is shown to exhibit the theoretical limit for sensitivity to pH change for a supramolecular polymerization system, with bidirectional response and maximum assembly occurring at physiological pH. Further control of the assembly process is demonstrated by employing polycyclic, planar molecules that stack on the rosette surface, effectively behaving as noncovalent terminators, which can be used to precisely tune the length of supramolecular polymers and the bulk properties of hydrogels. These studies also provide insight the origin of RNA, as the nucleobase-like heterocycles are shown to overcome challenges associated with prebiotic nucleic acid synthesis (e.g., spontaneous nucleoside formation in water and monomer selection/preorganization). Additionally, I report on the characterization of a DNA-based dynamic combinatorial system, as well as investigations that have enhanced our understanding of the nucleic acid backbone’s contribution to the binding of intercalators to oligonucleotide duplex assemblies.