Design of Abiological Digital Poly(phosphodiester)s

Abstract

Conspectus In biological systems, the storage and transfer of genetic information rely on sequence-controlled nucleic acids such as DNA and RNA. It has been realized for quite some time that this property is not only crucial for life but could also be very useful in human applications. For instance, DNA has been actively investigated as a digital storage medium over the past decade. Indeed, the “hard-disk of life” is an obvious choice and a highly optimized material for storing data. Through decades of nucleic acids research, technological tools for parallel synthesis and sequencing of DNA have been readily available. Consequently, it has already been demonstrated that different types of documents (e.g., texts, images, videos, and industrial data) can be stored in chemically synthesized DNA libraries. However, DNA is subject to biological constraints, and its molecular structure cannot be easily varied to match technological needs. In fact, DNA is not the only macromolecule that enables data storage. In recent years, it has been demonstrated that a wide variety of synthetic polymers can also be used for such a purpose. Indeed, modern polymer synthesis allows the preparation of synthetic macromolecules with precisely controlled monomer sequences. Altogether, about a dozens of synthetic digital polymers have already been described, and many more can be foreseen. Among them, sequence-defined poly­(phosphodiester)­s are one of the most promising options. These polymers are prepared by stepwise phosphoramidite chemistry like chemically synthesized oligonucleotides. However, they are constructed with non-natural building blocks and therefore share almost no structural characteristics with nucleic acids, except phosphate repeat units. Still, they contain readable digital messages that can be deciphered by nanopore sequencing or mass spectrometry sequencing. In this Account, we describe our recent research efforts in synthesizing and sequencing optimal abiological digital poly­(phosphodiester)­s. A major advantage of these polymers over DNA is that their molecular structure can easily be varied to tune their properties. During the last 5 years, we have engineered the molecular structure of these polymers to adjust crucial parameters such as the storage density, storage capacity, erasability, and readability. Consequently, high-capacity PPDE chains, containing hundreds of bits per chains, can now be synthesized and efficiently sequenced using a routine mass spectrometer. Furthermore, sequencing data can be automatically decrypted with the help of decoding software. This new type of coded matter can also be edited using practical physical triggers such as light and organized in space by programmed self-assembly. All of these recent improvements are summarized and discussed herein.

Crystallization-Driven Self-Assembly of Block Copolymers Having Monodisperse Poly(lactic acid)s with Defined Stereochemical Sequences

“…Inspired by the biological functions arising from the well-defined chemical structures of biopolymers, the synthesis of polymers without molecular weight distribution and sequence uncertainty has been pursued extensively in polymer chemistry. The synthesis of monodisperse polymers has relied mostly on the sequential addition of individual monomers via solid-phase synthesis. − However, with the increase in molecular weight or number of repeating units, their synthesis becomes difficult, which limits the availability of monodisperse polymers and the study of their properties. − Recent developments of synthetic strategies including the iterative exponential growth and the cross-convergent synthesis have allowed the synthesis of high-molecular-weight monodisperse polymers with defined sequences. − These advances have provided the opportunities to study the behavior of synthetic polymers with defined sequences and the absence of structural uncertainty. − Furthermore, monodisperse and sequence-defined polymers offer the opportunity to explore unprecedented applications of polymeric materials owing to the precisely defined chemical and physical properties dictated by their chemical structures. − …”

Chemical conjugation of nucleic acid aptamers and synthetic polymers

“…However, it has been recently demonstrated that this chemistry can also be used to prepare sequence-defined synthetic polymers. [88][89][90] Thus, iterative phosphoramidite chemistry is not only the gold standard method for DNA synthesis but also an interesting polymer chemistry tool. 91 Since this method can be applied to both phosphoramidite nucleosides and non-natural phosphoramidite monomers, it is a very convenient platform for the synthesis of bio-hybrid macromolecules containing both synthetic and DNA segments.…”

Synthesis and sequencing of informational poly(amino phosphodiester)s

“…They all contain a main-chain nitrogen atom and alkyl side-chain substituents of increasing size, namely methyl (M1), propyl (M2), pentyl (M3) and heptyl (M4). Following our laboratory convention, 19 monomers of increasing molar mass M1, M2, M3 and M4 represent binary dyads 00, 01, 10 and 11, respectively. Main-chain propyl spacers were intentionally placed between oxygen and nitrogen atoms in all these monomers.…”

“…tandem mass spectrometry, MS/MS), racemic synthons can be used to construct them. For instance, our group has reported the synthesis of digital poly(phosphodiester)s (d-PPDE), [17][18][19] in which a comonomer alphabet is used to write binary information. 20 These polymers are prepared by solid-phase phosphoramidite polymer chemistry (PPC); a versatile method that can be used for synthesis of biological (i.e.…”

“…[25][26][27][28] In all d-PPDE we have studied so far, the coded side-chains are attached to a main-chain carbon atom. 19 In order to avoid the formation of atactic polymers, symmetric carbons were used in our initial design. 17 Still, we have recently developed expanded alphabets, in which racemic building blocks were also used.…”