“Nano-oddities”: Unusual Nucleic Acid Assemblies for DNA-Based Nanostructures and Nanodevices

Abstract

CONSPECTUS: DNA is an attractive polymer building material for nanodevices and nanostructures due to its ability for self-recognition and self-assembly. Assembly relies on the formation of base-specific interactions that allow strands to adopt structures in a controllable fashion. Most DNA-based higher order structures such as DNA cages, 2D and 3D DNA crystals, or origamis are based on DNA double helices stabilized by Watson-Crick complementarity. A number of nonclassical pairing patterns are possible between or among DNA strands; these interactions result in formation of unusual structures that include, but are not limited to, G-quadruplexes, i-motifs, triplexes, and parallel-stranded duplexes. These structures create greater diversity of DNA-based building blocks for nanomaterials and have certain advantages over conventional duplex DNA, such as enhanced thermal stability and sensitivity to chemical stimuli. In this Account, we briefly introduce these alternative DNA structures and describe in detail their utilization in a variety of nanomaterials and nanomachines. The field of DNA "nano-oddities" emerged in the late 1990s when for the first time a DNA nanomachine was designed based on equilibrium between B-DNA and noncanonical, left-handed Z-DNA. Soon after, "proof-of-principle" DNA nanomachines based on several DNA "oddities" were reported. These machines were set in motion by the addition of complementary strands (a principle used by many B-DNA-based nanodevices), by the addition of selected cations, small molecules, or proteins, or by a change in pH or temperature. Today, we have fair understanding of the mechanism of action of these devices, excellent control over their performance, and knowledge of basic principles of their design. pH sensors and pH-controlled devices occupy a central niche in the field. They are usually based on i-motifs or triplex DNA, are amazingly simple, robust, and reversible, and create no waste apart from salt and water. G-quadruplex based nanostructures have unusually high stability, resist DNase and temperature, and display high selectivity toward certain cations. The true power of using these "nano-oddities" comes from combining them with existing nanomaterials (e.g., DNA origami, gold nanoparticles, graphene oxide, or mesoporous silica) and integrating them into existing mechanical and optoelectronic devices. Creating well-structured junctions for these interfaces, finding appropriate applications for the vast numbers of reported "nano-oddities", and proving their biological innocence comprise major challenges in the field. Our Account is not meant to be an all-inclusive review of the field but should give a reader a firm grasp of the current state of DNA nanotechnology based on noncanonical DNA structures.

Evaluation of the Stability of DNA i‐Motifs in the Nuclei of Living Mammalian Cells

“…These observations open an avenue for the identification of genomic C-rich sequences capable of forming stable i-motifs in vivo and provide essential information for the design and development of i-motif-based DNAn anodevices/biosensors for intracellular applications. [12] In biological terms,o ur results support the concept that i-motif structures may act as active regulators of genomic DNAa nd potential drug targets. [3,4,13] …”

Orienting Tetramolecular G‐Quadruplex Formation: The Quest for the Elusive RNA Antiparallel Quadruplex

“…Increasing evidence support biological roles for these oddities, [1,2] which may also find application in nanotechnologies [3] and biotechnologies (DNAzymes, aptamers…). [4,5] DNA quadruplexes are highly polymorphic: intramolecular structures may be parallel, antiparallel or "3+1" (three strands pointing in the same direction whereas the fourth one has the opposite polarity) although tetramolecular DNA quadruplexes tend to be all parallel.…”

“…[14] However, the construction of nanostructures based on non-canonical pairing is gaining importance and nanodevices based on motifs such as quadruplexes or triplexes have been described. [3] Both motifs (duplexes and quadruplexes) may be combined and the synapsis between duplexes and quadruplex structures have been shown at the molecular level [15,16] and have already been applied as a tool for the construction of nanomaterials [17,18] . In order to expand the applications of this hybrid duplexquadruplex structure, a deep understanding of their properties and folding process is required.…”

Structure of a left-handed DNA G-quadruplex

“…Recent studies demonstrated their existence in human cells (15) and their involvement in cellular regulation including recombination (12), replication (13,14), transcription (10), and translation (11). On the other hand, synthetic G4s have been introduced as unique structural elements in nanotechnology (20) as well as aptamers for therapeutic and diagnostic purposes (21). For instance, the G-rich oligonucleotide AGRO100 (SI Appendix, Table S1), also known as AS1411, has been shown to exhibit potent antiproliferative activity against a range of cancer cells (21) and was later found to adopt multiple G4 conformations (22).…”