Diverse Proteomimetic Frameworks via Rational Design of π-Stacking Peptide Tectons.

Peptide-based frameworks aim to integrate protein architecture into solid-state materials using simpler building blocks. Despite the growing number of peptide frameworks, there are few strategies to rationally engineer essential properties like pore size and shape. Designing peptide assemblies is generally hindered by the difficulty of predicting complex networks of weak intermolecular interactions. Peptides conjugated to polyaromatic groups are a unique case where assembly appears to be strongly driven by π-π interactions, suggesting that rationally adjusting the geometry of the π-stackers could create novel structures. Here, we report peptide elongation as a simple mechanism to predictably tune the angle between the π-stacking groups to produce a remarkable diversity of pore shapes and sizes, including some that are mesoporous. Notably, rapid jumps in pore size and shape can occur with just a single amino acid insertion. The geometry of the π-stacking residues also significantly influences framework structure, representing an additional dimension for tuning. Lastly, sequence identity can also indirectly modulate the π-π interactions. By correlating each of these factors with detailed crystallographic data, we find that, despite the complexity of peptide structure, the shape and polarity of the tectons are straightforward predictors of framework structure. These guidelines are expected to accelerate the development of advanced porous materials with protein-like capabilities.

Crystallography reveals metal-triggered restructuring of ß-hairpins.

Metal binding to ß-sheets occurs in many metalloproteins and is also implicated in the pathology of Alzheimer's disease. De novo designed metallo-ß-sheets have been pursued as models and mimics of these proteins. However, no crystal structures of canonical ß-sheet metallopeptides have yet been obtained, in stark contrast to many examples for ɑ-helical metallopeptides, leading to a poor understanding for their chemistry. To address this, we have engineered tryptophan zippers, stable 12-residue ß-sheet peptides, to bind Cu(II) ions and obtained crystal structures through single crystal X-ray diffraction (SC-XRD). We find that metal binding triggers several unexpected supramolecular assemblies that demonstrate the range of higher-order structures available to metallo-ß-sheets. Overall, these findings underscore the importance of crystallography in elucidating the rich structural landscape of metallo-ß-sheet peptides.

Peptide hydrogen-bonded organic frameworks.

Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity. Flexible, ultra-short peptide-based P-HPFs (composed of 3 or fewer amino acids) exhibit adaptable porous topologies that can accommodate a variety of guest molecules and capture hazardous greenhouse gases. Longer, folded peptides present challenges and opportunities in designing P-HPFs. This review highlights recent developments in P-HPFs using ultra-short peptides, folded peptides, and foldamers, showcasing their utility for gas storage, chiral recognition, chiral separation, and medical applications. It also addresses design challenges and future directions in the field.

Pore Restructuring of Peptide Frameworks by Mutations at Distal Packing Residues.

Porous framework materials are highly useful for catalysis, adsorption, and separations. Though they are usually made from inorganic and organic building blocks, recently, folded peptides have been utilized for constructing frameworks, opening up an enormous structure-space for exploration. These peptides assemble in a metal-free fashion using π-stacking, H-bonding, dispersion forces, and the hydrophobic effect. Manipulation of pore-defining H-bonding residues is known to generate new topologies, but the impact of mutations in the hydrophobic packing region facing away from the pores is less obvious. To explore their effects, we synthesized variants of peptide frameworks with mutations in the hydrophobic packing positions and found by single-crystal X-ray crystallography (SC-XRD) that they induce significant changes to the framework pore structure. These structural changes are driven by a need to maximize van der Waals interactions of the nonpolar groups, which are achieved by various mechanisms including helix twisting, chain flipping, chain offsetting, and desymmetrization. Even subtle changes to the van der Waals interface, such as the introduction of a methyl group or isomeric replacement, result in significant pore restructuring. This study shows that the dispersion interactions upholding a peptide material are a rich area for structural engineering.