Designed Metal-Containing Peptoid Membranes as Enzyme Mimetics for Catalytic Organophosphate Degradation

Abstract

The detoxification of lethal organophosphate (OP) residues in the environment is crucial to prevent human exposure and protect modern society. Despite serving as excellent catalysts for OP degradation, natural enzymes require costly preparation and readily deactivate upon exposure to environmental conditions. Herein, we designed and prepared a series of phosphotriesterase mimics based on stable, self-assembled peptoid membranes to overcome these limitations of the enzymes and effectively catalyze the hydrolysis of dimethyl p-nitrophenyl phosphate (DMNP)�a nerve agent simulant. By covalently attaching metal-binding ligands to peptoid N-termini, we attained enzyme mimetics in the form of surface-functionalized crystalline nanomembranes. These nanomembranes display a precisely controlled arrangement of coordinated metal ions, which resemble the active sites found in phosphotriesterases to promote DMNP hydrolysis. Moreover, using these highly programmable peptoid nanomembranes allows for tuning the local chemical environment of the coordinated metal ion to achieve enhanced hydrolysis activity. Among the crystalline membranes that are active for DMNP degradation, those assembled from peptoids containing bis-quinoline ligands with an adjacent phenyl side chain showed the highest hydrolytic activity with a 219-fold rate acceleration over the background, demonstrating the important role of the hydrophobic environment in proximity to the active sites. Furthermore, these membranes exhibited remarkable stability and were able to retain their catalytic activity after heating to 60 °C and after multiple uses. This work provides insights into the principal features to construct a new class of biomimetic materials with high catalytic efficiency, cost-effectiveness, and reusability applied in nerve agent detoxification.

Access to Advanced Functional Materials through Postmodification of Biomimetic Assemblies via Click Chemistry

“…For example, Jian et al reported highly stable peptoid nanotubes that exhibit peroxidase-like activity for lignin depolymerization . More recently, Trinh et al designed an enzyme-mimicking peptoid nanomembrane that contains metal-binding catalytic sites to degrade chemical warfare agent (CWA) simulants . In both studies, the authors emphasize the importance of modifying the local environment of the active sites to control the catalytic activity.…”

“…This key difference eliminates backbone hydrogen bonding, which in turn decreases structural complexity and enables the ability to tune molecular interactions exclusively through side-chain chemistry. Furthermore, the N-substitution increases peptoid stability against proteolysis and elevated temperature conditions. ,, Peptoids are commonly synthesized using the submonomer solid-phase synthesis method which enables an enormous diversity of side-chain chemistries. ,, Thus, a large number of peptoid sequences have been synthesized and exploited for the self-assembly of various nanostructures, such as nanomembranes, ,− nanosheets, nanotubes, − nanofibers, , and nanoribbons. , Due to ease of synthesis, peptoid submonomers could be sourced from many commercially available amines; thus, incorporating reactive moieties for facile conjugation reactions is highly attainable.…”

“…2D nanomaterials are fundamental structures that bridge a gap between low-dimensional and high-dimensional 3D structures. Compared to inorganic systems, 2D nanomaterials assembled from sequence-defined macromolecules offer tailorable features and biological functions. ,,, Specifically, peptide and peptoid nanosheets have been shown as a platform for studying cell membrane interactions, templating inorganic crystals, bioinspired catalysis, biosensors, and antibody mimetics. ,,,,, The self-assembly of peptide nanosheets arises from the secondary structure of peptide sequences, such as α-helices and β-sheets. ,, For example, Jang et al used peptides with an α-helix dimer conformation to assemble into 2D nanosheets . The heptapeptide YYACAYY is rich in tyrosine residues and assembled at an air/water interface.…”

“…In this method, molecules are designed to associate and self-assemble into well-defined nanostructures with diverse architectures and unique properties. In particular, sequence-defined synthetic polymers have been developed as the building blocks to fabricate tunable and robust biomimetic materials for applications in drug delivery, tissue engineering, biomineralization, molecular imaging, sensing, and water decontamination. − Among these sequence-defined macromolecules, synthetic peptides and their mimics (i.e., peptoids) have gained significant attention for nanomaterial fabrication due to their inherent high-information content, ease of synthesis, biocompatibility, and tunability. − Furthermore, access to advanced functional nanomaterials is of considerable interest, especially for achieving hybrid hierarchical structures composed of organic and inorganic constituents with multilength scales. ,,, Although there remains a challenge to precisely place discrete components (i.e., nanoparticles and biomacromolecules) on macromolecular assemblies and control their loading and local microenvironment, considerable progress has been made in the rational design of such complicated systems. − A key strategy for incorporating greater complexity into existing nanomaterials is realized via postsynthetic functionalization. ,,, This process refers to a self-assembling macromolecule that contains a reactive functional group, and once the assembled structure has formed, a second molecule is added to specifically react with that modification on the surface. The ability to covalently modify the chemistry on a material’s surface can tune the local environment, enhance stability, and, most importantly, impart functionality. ,,− Of the many existing covalent chemistries available, “click” chemistry is arguably the most powerful methodology at hand.…”

“…First, we introduce the well-established click chemistry toolbox, followed by briefly describing biomimetic building blocks for self-assembly and then elaborating on peptide- and peptoid-based self-assembly motifs. From there, we highlight recent advancements in using click chemistry to modify self-assemblies to enhance programmability as well as introduce functionality for various applications, such as molecular recognition, mineralization, and optoelectronics. , We also discuss some potential areas that could benefit from postmodification of macromolecular assemblies using click chemistry, such as enzyme mimetics for catalysis applications. , Finally, we conclude by indicating the vast potential of using well-studied chemistries to enrich biomimetic self-assemblies and achieve materials with designed functionalities. We hope this work will provide stimulation for new research to develop functional hybrid nanomaterials that bridge well-defined structures and facile covalent chemistry for a variety of applications.…”