The evolution of proteins from simpler, selfassembled peptides provides a powerful blueprint for the design of complex synthetic materials. Previously, peptide−metal frameworks using short sequences (≤3 residues) have shown great promise as proteomimetic materials that exhibit sophisticated capabilities. However, their development has been hindered due to few variable residues and restricted choice of side-chains that are compatible with metal ions. Herein, we developed a noncovalent strategy featuring π-stacking bipyridyl residues to assemble much longer peptides into crystalline frameworks that tolerate even previously incompatible acidic and basic functionalities and allow an unprecedented level of pore variations. Single-crystal X-ray structures are provided for all variants to guide and validate rational design. These materials exhibit hallmark proteomimetic behaviors such as guest-selective induced fit and assembly of multimetallic units. Significantly, we demonstrate facile optimization of the framework design to substantially increase affinity toward a complex organic molecule.
Metalloenzymes have benefited from the iterative process of evolution to achieve the precise arrangements of secondary sphere non-covalent interactions that enhance metal-centered catalysis. Iterative synthesis of scaffolds that display complex secondary sphere elements in abiotic systems can be highly challenging and time-intensive. To overcome this synthetic bottleneck, we developed a highly modular and rapid synthetic strategy, leveraging the efficiency of solid-phase peptide synthesis and conformational control afforded by non-canonical residues to construct a ligand platform displaying up to four unique residues of varying electronics and sterics in the secondary coordination sphere. As a proof-of-concept that peptidic secondary sphere can cooperate with the metal complex, we applied this scaffold to a well-known, modestly active C–H oxidizing Fe catalyst to evolve specific non-covalent interactions that is more than double its catalytic activity. Solution-state NMR structures of several catalyst variants suggest that higher activity is correlated with a hydrophobic pocket above the Fe center that may enhance the formation of a catalyst–substrate complex. Above all, we show that peptides are a convenient, highly modular, and structurally defined ligand platform for creating secondary coordination spheres that comprise multiple, diverse functional groups.
The inert nature of C(sp3)–H bonds makes their oxidative cleavage a difficult task. While metalloenzymes employ an array of non-covalent interactions to facilitate C(sp3)–H oxidation, this strategy is underexplored in abiotic catalysts due to time-consuming and low-yielding ligand syntheses, which impedes iterative design. To surmount these obstacles, we, herein, have developed a highly modular and rapid synthetic strategy that capitalizes on the efficiency of solid-phase peptide synthesis, which enables the generation of a ligand platform displaying at least four unique residues of varying electronics and sterics in the secondary coordination sphere of a C–H oxidizing Fe catalyst. Modulating the non-covalent interactions in seven variants significantly influences cyclohexane oxidation catalysis, with one variant that boosts the catalytic activity by more than two-fold. To better understand the catalytic trends, we have determined the catalysts’ solution-state structures by 2D NMR spectroscopy, which suggests that peptide conformation can control substrate access and binding. This work demonstrates that (1) tunable, diverse, and complex active sites can be made readily, and (2) these active sites can be optimized to significantly increase catalytic activity.
The inert nature of C(sp 3 )-H bonds makes their oxidative cleavage a difficult task. While metalloenzymes employ an array of non-covalent interactions to facilitate C(sp 3 )-H oxidation, this strategy is underexplored in abiotic catalysts due to time-consuming and lowyielding ligand syntheses, which impedes iterative design. To surmount these obstacles, we, herein, have developed a highly modular and rapid synthetic strategy that capitalizes on the efficiency of solid-phase peptide synthesis, which enables the generation of a ligand platform displaying at least four unique residues of varying electronics and sterics in the secondary coordination sphere of a C-H oxidizing Fe catalyst. Modulating the non-covalent interactions in seven variants significantly influences cyclohexane oxidation catalysis, with one variant that boosts the catalytic activity by more than two-fold. To better understand the catalytic trends, we have determined the catalysts' solution-state structures by 2D NMR spectroscopy, which suggests that peptide conformation can control substrate access and binding. This work demonstrates that (1) tunable, diverse, and complex active sites can be made readily, and (2) these active sites can be optimized to significantly increase catalytic activity.
The evolution of proteins from simpler, self-assembled peptides provides a powerful blueprint for the design of complex synthetic mate-rials. Previously, peptide–metal frameworks using short sequences (≤ 3 residues) have shown great promise as proteomimetic materials that exhibit sophisticated capabilities. However, their evolution has been hindered due to few mutable residues and restricted choice of side-chains that are compatible with metal ions. Herein, we developed a non-covalent strategy using π-stacking to assemble much longer peptides into crystalline frameworks that tolerate even previously incompatible acidic and basic functionalities, and allow an unprecedent-ed level of pore mutations. Single-crystal X-ray structures are provided for all mutants to guide and validate rational design. These materi-als exhibit hallmark protein behaviors such as guest-selective induced-fit and assembly of multi-metallic units. Significantly, we demon-strate facile evolution of the framework to substantially increase affinity towards a complex organic molecule.
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