Positive Allostery in Metal Ion Binding by a Cooperatively Folded β-Peptide Bundle

Abstract

Metal ion binding is exploited by proteins in nature to catalyze reactions, bind molecules, and favor discrete structures, but it has not been demonstrated in β-peptides or their assemblies. Here we report the design, synthesis, and characterization of a β-peptide bundle that uniquely binds two Cd(II) ions in a distinct bicoordinate array. The two Cd(II) ions bind with positive allosteric cooperativity and increase the thermodynamic stability of the bundle by more than 50 °C. This system provides a unique, synthetic context to explore allosteric regulation and should pave the way to sophisticated molecular assemblies with catalytic and substrate-sensing functions that have historically not been available to de novo designed synthetic proteomimetics in water.

Self‐Assembled Cyclic Structures from Copper(II) Peptoids

“…Indeed, metal–ligand coordination is one of the most used interactions to drive the self‐assembly of small molecules as well as of synthetic peptides and proteins into various 2D and 3D supramolecular architectures—spanning from macrocycles and other geometrical shapes to cages and metal‐organic frameworks (MOFs), lattices, discs, spherical shells or fibrils, and additional quaternary structures ,. In recent years, a variety of oligomeric sequences akin to peptides, namely peptidomimetic foldamers, capable of binding metal ions have been developed, and some enabled biomimetic functions such as selective recognition, allosteric cooperativity, and catalysis . An important class of peptidomimetic foldamers is peptoids—N‐substituted glycine oligomers—which are capable of various applications such as metal binding, catalysis, and in medicine .…”

Water‐soluble chiral metallopeptoids

“…Metallopeptoids, which are both chiral and water‐soluble, however, have not been described yet. A few other peptide mimics that bind metal ions were also reported, such as a β‐peptide hairpin that coordinates Zn(II) and a Cd(II) β‐peptide bundle …”

A prochelator peptide designed to use heterometallic cooperativity to enhance metal ion affinity

“… 23 Recently, a β-peptide bundle was shown to exhibit positive allosteric cooperativity in water for binding two Cd 2+ ions at distinct sites. 24 In these cases, cooperative metal binding serves to stabilize the overall construct for structural or catalytic purposes. In contrast, the goal for metal-activated prochelators is to influence the environment around the construct by altering metal concentrations in a synergistic way.…”