Enhancing β³‐Peptide Bundle Stability by Design

Abstract

We reported recently that certain β(3) -peptides self-assemble in aqueous solution into discrete bundles of unique structure and defined stoichiometry. The first β-peptide bundle reported was the octameric Zwit-1F, whose fold is characterized by a well-packed, leucine-rich core and a salt-bridge-rich surface. Close inspection of the Zwit-1F structure revealed four nonideal interhelical salt-bridge interactions whose heavy atom-heavy atom distances were longer than found in natural proteins of known structure. Here we demonstrate that the thermodynamic stability of a β-peptide bundle can be enhanced by optimizing the length of these four interhelical salt bridges. Combined with previous work on the role of internal packing residues, these results provide another critical step in the "bottom-up" formation of β-peptide assemblies with defined sizes, reproducible structures, and sophisticated function.

Relationship between side-chain branching and stoichiometry in β3-peptide bundles

“…3a). This behavior is characteristic of a concentration-dependent equilibrium between a partially structured monomer and a folded oligomer, and mimics the behavior of previously characterized β 3 -peptide bundles, whether octameric (Zwit-1F, Zwit-8L*, Acid-1Y, Zwit-EYYK, Acid-1Y LL , Acid-1Y LL* ) 1,2,5,6 or tetrameric (Zwit-VY and Acid-VY). 4 A plot of MRE 212 as a function of Acid-3Y concentration fit to a monomer-tetramer equilibrium model with ln K a = 35.7 ± 0.8 (Fig.…”

“…1–5 The β 3 -peptide bundles we described undergo cooperative, two-state folding transitions, exchange core amide protons slowly, and exclude hydrophobic dyes; the structures of five such bundles are known in atomic detail. 1,2,5,6 These initially reported octameric assemblies were designed without the benefit of high-resolution structural data, and were expected to assemble as dimers or tetramers. The observation of a discrete octameric array, with a hydrophobic core composed entirely of solvent-inaccessible β 3 -homoleucine residues, was unanticipated.…”

The Ant‐Pro Reverse‐Turn Motif. Structural Features and Conformational Characteristics

“…The consequences of configuration alteration in the conformation of reverse‐turn segments has been independently verified by the Yale group led by Scott J. Miller during their arduous campaign towards developing β‐hairpin templates36 for effecting stereospecific, enzyme‐like asymmetric catalysis 37. Their studies, which also lend support to the earlier findings of the Balaram group, suggest that (D)Pro‐Gly, in contrast to (L)Pro‐Gly, effectively stabilizes β‐hairpins 8d,20b. In fact, short model peptide sequences carrying the (L)Pro‐Gly motif show little evidence of β‐hairpin formation 20b.…”

Modulating the Nucleated Self‐Assembly of Tri‐β3‐Peptides Using Cucurbit[n]urils

“…[23,32,33] Distinct octameric bundles have been assembled when helical 12-mer b 3 -peptides were employed in which cationic and anionic side chainsw ere alternated on one helical face, whereas b 3 -homoleucine residues werei ntroduced on as econd helical face. [34,35] Although the assembly mechanism of shorter 3-mer b 3 -peptides has not been reported so far,n o attemptsh ave been made to modulate b 3 -peptide assembly by addition of molecular components duringt he nucleation. The ability to modulate the outcome of hierarchicallya ssem- bled structures could open up the ability to post-functionalize the structures and to employ assemblies of particular states as nanomaterials.…”