Sequence-defined Synthetic Polymers Research Articles

Hierarchical Self-Assembly of Multidimensional Functional Materials from Sequence-Defined Peptoids.

Hierarchical self-assembly represents a powerful strategy for the fabrication of functional materials across various length scales. However, achieving precise formation of functional hierarchical assemblies remains a significant challenge and requires a profound understanding of molecular assembly interactions. In this study, we present a molecular-level understanding of the hierarchical assembly of sequence-defined peptoids into multidimensional functional materials, including twisted nanotube bundles serving as a highly efficient artificial light harvesting system. By employing synchrotron-based powder X-ray diffraction and analyzing single crystal structures of model compounds, we elucidated the molecular packing and mechanisms underlying the assembly of peptoids into multidimensional nanostructures. Our findings demonstrate that incorporating aromatic functional groups, such as tetraphenyl ethylene (TPE), at the termini of assembling peptoid sequences promotes the formation of twisted bundles of nanotubes and nanosheets, thus enabling the creation of a highly efficient artificial light harvesting system. This research exemplifies the potential of leveraging sequence-defined synthetic polymers to translate microscopic molecular structures into macroscopic assemblies. It holds promise for the development of functional materials with precisely controlled hierarchical structures and designed functions.

Assembly of short amphiphilic peptoids into nanohelices with controllable supramolecular chirality.

A long-standing challenge in bioinspired materials is to design and synthesize synthetic materials that mimic the sophisticated structures and functions of natural biomaterials, such as helical protein assemblies that are important in biological systems. Herein, we report the formation of a series of nanohelices from a type of well-developed protein-mimetics called peptoids. We demonstrate that nanohelix structures and supramolecular chirality can be well-controlled through the side-chain chemistry. Specifically, the ionic effects on peptoids from varying the polar side-chain groups result in the formation of either single helical fiber or hierarchically stacked helical bundles. We also demonstrate that the supramolecular chirality of assembled peptoid helices can be controlled by modifying assembling peptoids with a single chiral amino acid side chain. Computational simulations and theoretical modeling predict that minimizing exposure of hydrophobic domains within a twisted helical form presents the most thermodynamically favorable packing of these amphiphilic peptoids and suggests a key role for both polar and hydrophobic domains on nanohelix formation. Our findings establish a platform to design and synthesize chiral functional materials using sequence-defined synthetic polymers.

Homogeneous Synthesis of Monodisperse Sequence-Defined Conjugated Oligomers by Temperature Cycling.

Sequence-defined synthetic oligomers and polymers provide unprecedented opportunities for polymer chemists to finely control properties such as chain folding, self-assembly, and optoelectronic performance of materials. However, absolute control over both chain-length and monomer sequence has been a long-standing "grand challenge" for decades. Herein, we report a novel strategy to synthesize monodisperse sequence-defined conjugated oligomers in a homogeneous manner by temperature cycling, thereby achieving single-monomer precision in conjugated polyheterocycles. A series of sequence-defined oligomers with up to twelve repeating units, four different monomers, and various sequences were successfully synthesized. Monomer sequence was also proved to affect optical properties. We believe this strategy not only exhibits general applicability to the synthesis of group 16 conjugated oligomers and polymers, but also has far-reaching potential for other polymer systems.

Nondestructive Sequencing of Enantiopure Oligoesters by Nuclear Magnetic Resonance Spectroscopy.

Sequence-defined synthetic oligomers and polymers are promising molecular media for permanently storing digital information. However, the information decoding process relies on degradative sequencing methods such as mass spectrometry, which consumes the information-storing polymers upon decoding. Here, we demonstrate the nondestructive decoding of sequence-defined oligomers of enantiopure α-hydroxy acids, oligo(l-mandelic-co-d-phenyl lactic acid)s (oMPs), and oligo(l-lactic-co-glycolic acid)s (oLGs) by 13C nuclear magnetic resonance spectroscopy. We were able to nondestructively decode a bitmap image (192 bits) encoded using a library of 12 equimolar mixtures of an 8-bit-storing oMP and oLG, synthesized through semiautomated flow chemistry in less than 1% of the reaction time required for the repetition of conventional batch reactions. Our results highlight the potential of bundles of sequence-defined oligomers as efficient media for encoding and decoding large-scale information based on the automation of their synthesis and nondestructive sequencing processes.

Sequence-Defined Synthetic Polymers for New-Generation Functional Biomaterials

Sequence-Defined Synthetic Polymers for New-Generation Functional Biomaterials

Hierarchical Nanomaterials Assembled from Peptoids and Other Sequence-Defined Synthetic Polymers.

In nature, the self-assembly of sequence-specific biopolymers into hierarchical structures plays an essential role in the construction of functional biomaterials. To develop synthetic materials that can mimic and surpass the function of these natural counterparts, various sequence-defined bio- and biomimetic polymers have been developed and exploited as building blocks for hierarchical self-assembly. This review summarizes the recent advances in the molecular self-assembly of hierarchical nanomaterials based on peptoids (or poly-N-substituted glycines) and other sequence-defined synthetic polymers. Modern techniques to monitor the assembly mechanisms and characterize the physicochemical properties of these self-assembly systems are highlighted. In addition, discussions about their potential applications in biomedical sciences and renewable energy are also included. This review aims to highlight essential features of sequence-defined synthetic polymers (e.g., high stability and protein-like high-information content) and how these unique features enable the construction of robust biomimetic functional materials with high programmability and predictability, with an emphasis on peptoids and their self-assembled nanomaterials.

Sequence-defined l-glutamamide oligomers with pendant supramolecular motifs via iterative synthesis and orthogonal post-functionalization

One of the great challenges in polymer chemistry is to achieve discrete and sequence-defined synthetic polymers that fold in defined conformations and form well-defined three-dimensional structured particles.

Phosphoramitoids-A submonomer approach to sequence defined N-substituted phosphoramidate polymers.

There is a growing interest in new methods to generate bio-inspired, chemically diverse, sequence-defined synthetic polymers. Solid-phase submonomer approaches offer facile access to these types of materials, since they take advantage of readily available synthons. Submonomer approaches to date have been applied to peptidomimetics with oligo-amide backbones. Here we extend the approach to a phosphorous-containing backbone, where N-substituted phosphoramidate oligomers are constructed from a set of amine submonomers, diphenyl H-phosphonate, and cyclohexane diol. The key chemical steps in chain elongation are a chain extension reaction based on H-phosphonate (P III) chemistry, and a side chain attachment step based on the Atherton-Todd reaction. Cheap, stable chemical reagents are used without heating, all reaction times are 30 minutes or less and open to air, and no main-chain protecting groups are required. Phosphoramitoid tetramers and pentamers displaying a variety of side chain functionalities were synthesized by a three-step solid-phase submonomer method, typically with >85% crude purities.

Solid-phase synthesis of three-armed star-shaped peptoids and their hierarchical self-assembly.

Due to the branched structure feature and unique properties, a variety of star-shaped polymers have been designed and synthesized. Despite those advances, solid-phase synthesis of star-shaped sequence-defined synthetic polymers that exhibit hierarchical self-assembly remains a significant challenge. Hence, we present an effective strategy for the solid-phase synthesis of three-armed star-shaped peptoids, in which ethylenediamine was used as the centric star pivot. Based on the sequence of monomer addition, a series of AA'A''-type and ABB'-type peptoids were synthesized and characterized by UPLC-MS (ultrahigh performance liquid chromatography-mass spectrometry). By taking advantage of the easy-synthesis and large side-chain diversity, we synthesized star-shaped peptoids with tunable functions. We further demonstrated the aqueous self-assembly of some representative peptoids into biomimetic nanomaterials with well-defined hierarchical structures, such as nanofibers and nanotubes. These results indicate that star-shaped peptoids offer the potential in self-assembly of biomimetic nanomaterials with tunable chemistries and functions.

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving.

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid-phase synthesis and selective molecular sieving. The polymer is assembled in solution with real-time monitoring to ensure couplings proceed to completion, on a three-armed star-shaped macromolecule to maximize efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with side-arms at precisely defined locations that can undergo site-selective modification after polymerization. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.

Evolution of sequence-defined highly functionalized nucleic acid polymers.

The evolution of sequence-defined synthetic polymers made of building blocks beyond those compatible with polymerase enzymes or the ribosome has the potential to generate new classes of receptors, catalysts, and materials. Here we describe a ligase-mediated DNA-templated polymerization system and in vitro selection to evolve highly functionalized nucleic acid polymers (HFNAPs) made from 32 building blocks containing eight chemically diverse side-chains on a DNA backbone. Through iterated cycles of polymer translation, selection, and reverse translation, we discovered HFNAPs that bind PCSK9 and IL-6, two protein targets implicated in human diseases. Mutation and reselection of an active PCSK9-binding polymer yielded evolved polymers with high affinity (KD = 3 nM). This evolved polymer potently inhibited binding between PCSK9 and the LDL receptor. Structure-activity relationship studies revealed that specific side-chains at defined positions in the polymers are required for binding to their respective targets. Our findings expand the chemical space of evolvable polymers to include densely functionalized nucleic acids with diverse, researcher-defined chemical repertoires.

Highly stable and self-repairing membrane-mimetic 2D nanomaterials assembled from lipid-like peptoids.

An ability to develop sequence-defined synthetic polymers that both mimic lipid amphiphilicity for self-assembly of highly stable membrane-mimetic 2D nanomaterials and exhibit protein-like functionality would revolutionize the development of biomimetic membranes. Here we report the assembly of lipid-like peptoids into highly stable, crystalline, free-standing and self-repairing membrane-mimetic 2D nanomaterials through a facile crystallization process. Both experimental and molecular dynamics simulation results show that peptoids assemble into membranes through an anisotropic formation process. We further demonstrated the use of peptoid membranes as a robust platform to incorporate and pattern functional objects through large side-chain diversity and/or co-crystallization approaches. Similar to lipid membranes, peptoid membranes exhibit changes in thickness upon exposure to external stimuli; they can coat surfaces in single layers and self-repair. We anticipate that this new class of membrane-mimetic 2D nanomaterials will provide a robust matrix for development of biomimetic membranes tailored to specific applications.

Sequence‐Defined Oligomers from Hydroxyproline Building Blocks for Parallel Synthesis Applications

The functionality of natural biopolymers has inspired significant effort to develop sequence-defined synthetic polymers for applications including molecular recognition, self-assembly, and catalysis. Conjugation of synthetic materials to biomacromolecules has played an increasingly important role in drug delivery and biomaterials. We developed a controlled synthesis of novel oligomers from hydroxyproline-based building blocks and conjugated these materials to siRNA. Hydroxyproline-based monomers enable the incorporation of broad structural diversity into defined polymer chains. Using a perfluorocarbon purification handle, we were able to purify diverse oligomers through a single solid-phase extraction method. The efficiency of synthesis was demonstrated by building 14 unique trimers and 4 hexamers from 6 diverse building blocks. We then adapted this method to the parallel synthesis of hundreds of materials in 96-well plates. This strategy provides a platform for the screening of libraries of modified biomolecules.

Surface-Directed Assembly of Sequence-Defined Synthetic Polymers into Networks of Hexagonally Patterned Nanoribbons with Controlled Functionalities.

The exquisite self-assembly of proteins and peptides in nature into highly ordered functional materials has inspired innovative approaches to the design and synthesis of biomimetic materials. While sequence-defined polymers hold great promise to mimic proteins and peptides for functions, controlled assembly of them on surfaces still remains underdeveloped. Here, we report the assembly of 12-mer peptoids containing alternating acidic and aromatic monomers into networks of hexagonally patterned nanoribbons on mica surfaces. Ca(2+)-carboxylate coordination creates peptoid-peptoid and peptoid-mica interactions that control self-assembly. In situ atomic force microscopy (AFM) shows that peptoids first assemble into discrete nanoparticles; these particles then transform into hexagonally patterned nanoribbons on mica surfaces. AFM-based dynamic force spectroscopy studies show that peptoid-mica interactions are much stronger than peptoid-peptoid interactions, illuminating the driving forces for mica-directed peptoid assembly. We further demonstrate the display of functional domains at the N-terminus of assembling peptoids to produce extended networks with similar hierarchical structures. This research demonstrates that surface-directed peptoid assembly can be used as a robust platform to develop biomimetic coating materials for applications.

Design, Synthesis, Assembly, and Engineering of Peptoid Nanosheets.

Two-dimensional (2D) atomically defined organic nanomaterials are an important material class with broad applications. However, few general synthetic methods exist to produce such materials in high yields and to precisely functionalize them. One strategy to form ordered 2D organic nanomaterials is through the supramolecular assembly of sequence-defined synthetic polymers. Peptoids, one such class of polymer, are designable bioinspired heteropolymers whose main-chain length and monomer sequence can be precisely controlled. We have recently discovered that individual peptoid polymers with a simple sequence of alternating hydrophobic and ionic monomers can self-assemble into highly ordered, free-floating nanosheets. A detailed understanding of their molecular structure and supramolecular assembly dynamics provides a robust platform for the discovery of new classes of nanosheets with tunable properties and novel applications. In this Account, we discuss the discovery, characterization, assembly, molecular modeling, and functionalization of peptoid nanosheets. The fundamental properties of peptoid nanosheets, their mechanism of formation, and their application as robust scaffolds for molecular recognition and as templates for the growth of inorganic minerals have been probed by an arsenal of experimental characterization techniques (e.g., scanning probe, electron, and optical microscopy, X-ray diffraction, surface-selective vibrational spectroscopy, and surface tensiometry) and computational techniques (coarse-grained and atomistic modeling). Peptoid nanosheets are supramolecular assemblies of 16-42-mer chains that form molecular bilayers. They span tens of microns in lateral dimensions and freely float in water. Their component chains are highly ordered, with chains nearly fully extended and packed parallel to one another as a result of hydrophobic and electrostatic interactions. Nanosheets form via a novel interface-catalyzed monolayer collapse mechanism. Peptoid chains first assemble into a monolayer at either an air-water or oil-water interface, on which peptoid chains extend, order, and pack into a brick-like pattern. Upon mechanical compression of the interface, the monolayer buckles into stable bilayer structures. Recent work has focused on the design of nanosheets with tunable properties and functionality. They are readily engineerable, as functional monomers can be readily incorporated onto the nanosheet surface or into the interior. For example, functional hydrophilic "loops" have been displayed on the surfaces of nanosheets. These loops can interact with specific protein targets, serving as a potentially general platform for molecular recognition. Nanosheets can also bind metal ions and serve as 2D templates for mineral growth. Through our understanding of the formation mechanism, along with predicted features ascertained from molecular modeling, we aim to further design and synthesize nanosheets as robust protein mimetics with the potential for unprecedented functionality and stability.

PH-controlled DNA- and RNA-templated assembly of short oligomers.

In the area of artificial genetics the development of non-enzymatic self-organization of synthetic building blocks is critical for both providing biopolymers with extended functions and understanding prebiotic processes. While reversibility is believed to have played a major role in early functional genetic materials, we previously reported an efficient DNA-templated ligation of suitably designed 5'-end boronic acid and 3'-end ribonucleosidic half-sequences. Here, we report the enzyme-free and activation-free DNA- and RNA-templated assembly of bifunctional hexamers. The reversible assembly was found to be regio- and sequence specific and the stabilities of the resulting duplexes were compared to their nicked counterparts. To go further with our understanding of this unprecedented process we also examined an auto-templated duplex self-assembly representing a key step toward the evolution of sequence-defined synthetic polymers.

Enzyme-free translation of DNA into sequence-defined synthetic polymers structurally unrelated to nucleic acids

The translation of DNA sequences into corresponding biopolymers enables the production, function, and evolution of the macromolecules of life. In contrast, methods to generate sequence-defined synthetic polymers with similar levels of control have remained elusive. Here we report the development of a DNA-templated translation system that enables the enzyme-free translation of DNA templates into sequence-defined synthetic polymers that have no necessary structural relationship with nucleic acids. We demonstrate the efficiency, sequence-specificity, and generality of this translation system by oligomerizing building blocks including polyethylene glycol (PEG), α-(d)-peptides, and β-peptides in a DNA-programmed manner. Sequence-defined synthetic polymers with molecular weights of 26 kDa containing 16 consecutively coupled building blocks and 90 densely functionalized β-amino acid residues were translated from DNA templates using this strategy. We integrated the DNA-templated translation system developed here into a complete cycle of translation, coding sequence replication, template regeneration, and re-translation suitable for the iterated in vitro selection of functional sequence-defined synthetic polymers unrelated in structure to nucleic acids.

DNA-Templated Polymerization of Side-Chain-Functionalized Peptide Nucleic Acid Aldehydes

The DNA-templated polymerization of synthetic building blocks provides a potential route to the laboratory evolution of sequence-defined polymers with structures and properties not necessarily limited to those of natural biopolymers. We previously reported the efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid (PNA) aldehydes. Here, we report the enzyme-free, DNA-templated polymerization of side-chain-functionalized PNA tetramer and pentamer aldehydes. We observed that polymerization of tetramer and pentamer PNA building blocks with a single lysine-based side chain at various positions in the building block could proceed efficiently and sequence specifically. In addition, DNA-templated polymerization also proceeded efficiently and in a sequence-specific manner with pentamer PNA aldehydes containing two or three lysine side chains in a single building block to generate more densely functionalized polymers. To further our understanding of side-chain compatibility and expand the capabilities of this system, we also examined the polymerization efficiencies of 20 pentamer building blocks each containing one of five different side-chain groups and four different side-chain regio- and stereochemistries. Polymerization reactions were efficient for all five different side-chain groups and for three of the four combinations of side-chain regio- and stereochemistries. Differences in the efficiency and initial rate of polymerization correlate with the apparent melting temperature of each building block, which is dependent on side-chain regio- and stereochemistry but relatively insensitive to side-chain structure among the substrates tested. Our findings represent a significant step toward the evolution of sequence-defined synthetic polymers and also demonstrate that enzyme-free nucleic acid-templated polymerization can occur efficiently using substrates with a wide range of side-chain structures, functionalization positions within each building block, and functionalization densities.