A bio-inspired approach to ligand design: folding single-chain peptoids to chelate a multimetallic cluster

Abstract

Synthesis of biomimetic multimetallic clusters is sought after for applications such as efficient storage of solar energy and utilization of greenhouse gases. However, synthetic efforts are hampered by a dearth of ligands that are developed for multimetallic clusters due to current limitations in rational design and organic synthesis. Peptoids, a synthetic sequence-defined oligomer, enable a biomimetic strategy to rapidly synthesize and optimize large, multifunctional ligands by structural design and combinatorial screening. Here we discover peptoid oligomers (≤7 residues) that fold into a single conformation to provide unprecedented tetra- and hexadentate chelation by carboxylates to a [Co₄O₄] cubane cluster. The structures of peptoid-bound cubanes were determined by 2D NMR spectroscopy, and their structures reveal key steric and side-chain-to-main chain interactions that work in concert to rigidify the peptoid ligand. This efficient ligand design strategy holds promise for creating new scaffolds for the abiotic synthesis and manipulation of multimetallic clusters.

Fig. 1. To faithfully reproduce the multimetallic cluster active site in a simplified environment, chelating ligands must be developed to control the coordination and assembly of the cluster. Peptoids have biomimetic structural and synthetic properties that enable discovery of such cluster-chelating ligands.

Fig. 2. (a) Selected amino acid residues from the D1 subunit (blue) that bind to the Mn₄Ca oxygen-evolving complex (OEC). (b) Design of the peptoid analogues based on D1. (c) Ensemble of the five lowest energy NMR structures of 1-2B (pyridine ligands omitted for clarity). (d) The lowest energy structure of 1-2B.

Fig. 3. (a) The φ and ψ dihedrals of a peptoid. (b) Backbone dihedral combinations (φ, ψ) of the lowest energy NMR structure for 1-2B (triangles) overlaid on the cis-peptoid Ramachandran free energy plot.

Fig. 4. (a) Primary sequence of peptoid H₃C. (b) Overlay of the five lowest energy NMR structures, with pyridine and acetate removed for clarity. (c) Peptoid backbone view only. (d) A selected low energy NMR structure.

Fig. 5. Backbone dihedral combinations (φ, ψ) of the lowest energy NMR structure for 1-C (triangles) overlaid on the cis-peptoid Ramachandran free energy plot. The residue numbers are indicated.

Fig. 6. (a) Close-up view of the loop region of 1-C. The loop residues are highlighted with green carbon atoms and labeled. The dashed line indicates the H-bond donor–acceptor distance. (b) LCMS of the crude reaction mixture between 1 and the mutated loop derivatives of H₃C (both 0.5 mM) in methanol after 20 h at 50 °C. The asterisk (*) indicates residual 1, and the red circle indicates peaks with masses corresponding to the hexadentate chelated cluster. Mobile phase: 5–95% gradient of acetonitrile/water with 10 mM NH₄OAc/HOAc (pH ∼ 5.2) buffer.