Relationship between Side Chain Structure and 14-Helix Stability of β³-Peptides in Water

Abstract

Folded polymers are used in Nature for virtually every vital process. Nonnatural folded polymers, or foldamers, have the potential for similar versatility, and the design and refinement of such molecules is of considerable current interest. Here we report a complete and systematic analysis of the relationship between side chain structure and the 14-helicity of a well-studied class of foldamers, β 3 -peptides, in water. Our experimental results (1) verify the importance of macrodipole stabilization for maintaining 14-helix structure, (2) provide comprehensive evidence that β 3 -amino acids branched at the first side chain carbon are 14-helix-stabilizing, (3) suggest a novel role for side chain hydrogen bonding as an additional stabilizing force in β 3 -peptides containing β 3 -homoserine or β 3 -homothreonine, and (4) demonstrate that diverse functionality can be incorporated into a stable 14-helix. Gas-and solution-phase calculations and Monte Carlo simulations recapitulate the experimental trends only in the context of oligomers, yielding insight into the mechanisms behind 14-helix folding. The 14-helix propensities of β 3 -amino acids differ starkly from the α-helix propensities of analogous α-amino acids. This contrast informs current models for α-helix folding, and suggests that 14-helix folding is governed by radically different biophysical forces than is α-helix folding. The ability to modulate 14-helix structure through side chain choice will assist rational design of 14-helical β-peptide ligands for macromolecular targets.Folded polymers are used in Nature for virtually every vital process, from catalysis to information storage, from cellular signaling to molecular transport. Nonnatural folded polymers, or foldamers, 1 have the potential for similar versatility, and the design and refinement of such molecules is of considerable current interest. [1][2][3] Previous studies of natural polymers -peptides, proteins, and nucleic acids -have shown that polymer folding is an extremely subtle process, governed by countless interactions among the backbone, side chains, and solvent. Nevertheless, control of foldamer structure is crucial if these molecules are to realize their full potential as tools in biology and medicine.A key element of foldamer design is therefore the ability to predict the folded structure of a given backbone and modulate this structure by altering the backbone and/or side chains. 1,3 In this respect, β-peptides are perhaps the best-characterized foldamers, as they populate a wide array of secondary structures including helices, sheets, and reverse turns. 1,4,5 are named for the number of atoms in a hydrogen-bonded ring and include the 10-helix, the 10/12-helix, the 12-helix, and the 14-helix ( Figure 1A). Helix type is largely determined by choice of β-amino acid monomer: cyclic ring constraints within the monomer of four atoms, five atoms, or six atoms promote the 10-helix, 12-helix, and 14-helix, respectively, 6-9 while acyclic, monosubstituted residues (β 2 -and β 3 -residues) te...

The Influence of Secondary Structure on Electron Transfer in Peptides

“…[13] b-Peptides were used in this study as they are known to adopt helical secondary structures with high predictability, structural diversity, and stability. [14][15][16][17][18] These structures are ideal for studying the fundamental mechanisms of electron transport, but they have as yet received scant attention. In this case, an N-terminal tert-butyl hydroperoxide was used as the electron acceptor and a C-terminal p-cyanobenzamide as the donor.…”

Solution Structure of a β-Peptide Ligand for hDM2

“…Overall, interactions among the three β 3 V side chains bury 155 ± 13 Å 2 of hydrophobic surface area from water (24% of the surfaces of these side chains). These packing interactions may explain why these and other branched residues stabilize 14-helices 12,18,19 and suggest new avenues for the design of 14-helix bundles. 20,21 The remaining 14-helix face consists of residues that comprise the hDM2-binding epitope, namely, β 3 -homoleucine (β 3 L3), β 3 -homotryptophan (β 3 W6), and β 3 -homophenylalanine (β 3 F9).…”

Biophysical and Structural Characterization of a Robust Octameric β-Peptide Bundle

“…9 β-Peptides, in particular oligomers of β 3 -amino acids, are a class of non-proteinaceous material with considerable potential for the development of unique quaternary structures. [9][10][11][12] When properly designed, β 3 -peptides assemble into stable, monomeric, 3 14 -helical structures in water, a first step toward formation of stable quaternary structures. Structural features that promote stable 3 14 -helices include alternating cationic and anionic side chains arranged on one helical face to support salt bridge formation [13][14][15] and arranged to minimize the helix macrodipole.…”

“…Structural features that promote stable 3 14 -helices include alternating cationic and anionic side chains arranged on one helical face to support salt bridge formation [13][14][15] and arranged to minimize the helix macrodipole. 12,16,17 Indeed, β 3 -peptides that embody these features tolerate extensive substitution of the remaining two helix faces 12,17,18 to generate highly protease-resistant 19 molecules that inhibit interactions between proteins both in vitro 18,20,21 and in cell-based assays. 22 Importantly, the inherent conformational flexibility of β 3 -peptides, when compared to cyclic analogues such as ACHC, 23 may be essential to the general success of this approach, as all β 3 -peptides of known structure that effectively inhibit protein interactions possess geometries that deviate from the ideal 3 14 -helix imposed by ACHC.…”