For much of the 20th century, molecular biologists, such as the famous team of James Watson and Francis Crick, studied and discovered chemical methods that could be used for the sequencing of both nucleic acids and proteins.
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While this work provided a considerable amount of information on monomer sequence regulation, it also demonstrated the need for polymer chemistry to further advance this area of science. In fact, polymer scientists are now acutely aware of the importance of monomer sequence control in the development and design of manmade materials.
Sequence-Specific Polymers and Nanostructures
Sequence-specific polymer strands have a unique capacity to selectively assemble into complex folded structures and multimeric complexes. Much of this assembly is dependent upon the residue sequences of these strands, which can include nucleic acids for the production of nanostructures.
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Nucleic acids have been shown to provide highly versatile properties that can produce self-assembling nanostructures through the hybridization of complementary strands. Despite these capabilities, the use of nucleic acids as nanoconstruction media is associated with both thermal and mechanical instability as a result of the weak hydrogen bonds that hold the resultant structures together.
Improving Self-Assembly Processes
Several attempts have been made to improve the stability of double-stranded nucleic acid-like duplexes. For example, certain studies have investigated how the integration of abiotic neutral backbones, isostere nucleobase mimetics, or photo-induced cross-links could reduce the intermolecular interactions needed to maintain the integrity of these nanostructures without compromising on important material properties.
Dynamic covalent interactions have also demonstrated a unique ability to not only mediate molecular self-assembly processes, but also ensure the production of robust and covalently cross-linked structures. While promising, many of these interactions experience slow reaction rates and limited accessibility to reaction sites, which, taken together, contribute to the kinetic trapping of non-equilibrium species.
In an effort to overcome these limitations, a recent study published in Nature Communications investigated a novel dynamic covalent self-assembly process used to produce multiple unique oligomers that bear covalent co-reactivity between amine- and aldehyde-based pendant groups.
This unique covalent attraction allows for these groups to selectively associate and dimerize with their oligomeric complements to ultimately create molecular ladders with imine-based covalent rungs. Taken together, this unique self-assembly process creates nanostructures that practically mimic the information-directed hybridization process of matching complementary biological nucleic acid sequences.
Novel Dynamic Covalent Self-Assembly Production of Oligomers
In their work, peptoids, which are inherently neutral and achiral structures that lack hydrogen bond donor sites, served as the precursor oligomers. The peptoids were then synthesized by a sub-monomer approach to solid-phase synthesis and served as the backbone for the dynamic covalent assembly of encoded molecular ladders.
Moreover, this peptoid synthesis resulted in the synthesis of alternating binary sequences of both amine and aldehyde pendant groups that eventually arose as a zig-zag strand conformation. This unique conformation allowed for inert spacer residues to arise between the pendant groups, which contributed to a greater level of solubility for both the precursor peptoids and their hybridized molecular ladders.
By improving the solubility of this structure, precipitation during the self-assembly process was avoided. Further protection of the aldehyde groups was achieved through the addition of ethylene acetals, which assisted in preventing the premature reaction of the pendant groups during both oligomer synthesis and purification.
Once the oligomers were synthesized, these molecules underwent simultaneous sequence-selective hybridization with their complementary strands. This process allowed for biomimetic and in-registry molecular ladders with imine-based covalent rungs to emerge as the primary reaction products.
Further exploration of this model was performed to assess its potential for information retrieval and storage purposes. To study this, binary-encoded peptoid sequences and a library of unpaired mass-labeled oligomers were used as messages.
Selective hybridization of these messages with their complementary sequences was found to successfully produce molecular ladders that allowed blinded researchers to determine the message by mass spectrometry. This information, therefore, demonstrated the ability of this model to accurately convey information that was in the presence of competitive binding species.
Applications in Electronics and Body Tissues
The dynamic covalent oligomer assembly system described here is expected to revolutionize the way in which molecular electronics are engineered. Otherwise referred to as molelectronics, these devices incorporate molecules between metal electrodes to allow for electron transport to be conducted between these molecular structures. Some of the most common applications of molelectronics include conducting polymers, photochromics, organic superconductors, electrochromics, and several others.
In addition to its usefulness in the assembly of molelectronics, this covalent oligomer synthesis process is expected to change the way in which prosthetic devices communicate with human tissues. Outside of prosthetics, self-replicating polymeric oligomers can also advance the current understanding of regenerative biomaterials to ultimately create a new pathway in the continuously changing field of regenerative medicine.
References and Further Reading
Lutz, J. (2017). Chapter 1 An Introduction to Sequence-Controlled Polymers. American Chemical Society.
Leguizamon, S. C., & Scott, T. F. (2020). Sequence-selective dynamic covalent assembly of information-bearing oligomers. Nature Communications 11(784). DOI: 10.1038/s41467-020-14607-3.
Lutz, J. (2017. Defining the Field of Sequence-Controlled Polymers. Macromolecular Rapid Communications 38(24). DOI: 10.1002/marc.201700582.
Mathew, P. T., & Fang, F. (2018). Advances in Molecular Electronics: A Brief Review. Engineering 4(6); 760-771. DOI: 10.1016/j.eng.2018.11.001.