Structural and functional studies of peptide/peptoid-based molecular systems mimicking natural enzymes

Abstract

Natural enzymes have been of great interest in discovering biomimetic or bioinspired materials for sustainable development. The highly efficient functions observed in enzymes originate from the stabilization of intermediates via the structural optimizations in the active site and protein matrix. Thus, a molecular system that can mimic natural enzymes' chemical and structural properties is desired in investigating biomimetic material science. While numerous efforts exist to mimic enzymes using various molecular systems, including organic small molecules or polymers, the installations of the unique properties found in enzymes (e.g., the monodispersity, intrinsic flexibility and folding structures) are still challenging. In chapter 1, the present works suggested peptides and peptoids as molecular systems that can implement the natural strategies of enzymes, owing to the enzyme-like properties of these biopolymers, including sequence-specificity, sufficient molecular diversity, and various secondary structures. In chapters 2–4, the active sites of metalloenzymes and metallopeptides, where transition metals successfully mediate redox reactions, were investigated to provide the design principles for metal redox catalysts and metallodrugs. Chapter 2 introduced an oxazole-containing amino acid as a unique histidine surrogate, which can substitute histidine residues of natural Cu(II)-binding motifs, such as the amino-terminal Cu- and Ni-binding motif (ATCUN, X-Z-H). Substituting the histidine residue in ATCUN motif with the oxazole-containing amino acid accelerated reactive oxygen species (ROS) generation by unlocking Cu(I)-mediated reaction mechanisms, which are less available with natural ATCUN peptides. In chapter 3, daptomycin, a peptide antibiotic, was repurposed for construction of multimetallic clusters. Cu(II)-daptomycin complexes exhibited up to four Cu(II) bindings and cooperative rate enhancement for O–O bond activation reactions (i.e., multicopper oxidase- and catalase-like activity) and O–O bond formation reactions (i.e., oxygen-evolving complex-like activity). Chapter 4 described the post-synthetic modifications of peptoids based on simple substitution reactions to mimic the histidine-rich metal binding sites in natural metalloenzymes. The facile modification of peptoids enabled the discovery of Cu(II)- and Fe(III)-binding cyclic peptoids, forming transparent film composed of metallopeptoids. Secondary structures are found in the protein matrix and associated with the natural quantum phenomena that facilitate ultrafast electron or energy transfers in enzymes by controlling the distance and arrangement of cofactors or prosthetic groups. Chapter 5 introduced a peptoid helix scaffold as a protein matrix analog to position electron donor (N,N-dimethylaniline) and acceptor (phenanthrene) moieties at a defined distance and arrangement. Herein, (phenylphenanthrene)-(phenyl-N,N-dimethylaniline)-peptoid conjugates (PhD-PCs) were developed, and the magnetic field effect (MFE) on the exciplex emission (ExE) between phenylphenanthrene and phenyl-N,N-dimethylaniline moieties on peptoids were investigated. Peptoid scaffolds allowed the exciplex systems to present MFE with a broader range of available solvents in applications (solvent dielectric constant (εr) = 4–67) compared to previous systems (εr = 11–47), providing a useful design principle able to determine initial photo-induced species, which was challenging with conventional dyad systems based on organic molecules. Chapter 6 explored incorporating a stable radical moiety (1,3-bis(diphenylene)-2-phenylallyl radical, BDPA·) into a peptoid helix scaffold as BDPA· has been of great interest in developing multispin organic molecules and materials based on controlling spin-spin interactions. In this chapter, multispin systems on peptoids helices were demonstrated by incorporating BDPA· into PhD-PCs, which have the potential to be used in developing molecular quantum teleportation systems by reading quantum information from molecular qubits (e.g., electron spin states of radical ion pairs generated by photoexcitation of electron donor and acceptor dyad). Inspired by the active sites of metalloenzymes and the protein secondary structure, a variety of peptide- and peptoid-based molecular systems capable of producing ROS, electrochemically splitting water, sensing magnetic fields, and constructing multispin systems were introduced in this thesis. The present works increased the chemical diversity of peptides and peptoids by developing synthetic methods to construct these functional entities. We hope that the structural and functional studies for these molecular systems will contribute to designing future biomimetic materials in investigating metallodrugs, redox catalysts, and molecular qubits.