Rotamer Libraries for the High-Resolution Design of β-Amino Acid Foldamers

Abstract

SUMMARY β-Amino acids offer attractive opportunities to develop biologically active peptidomimetics, either employed alone or in conjunction with natural α-amino acids. Owing to their potential for unique conformational preferences that deviate considerably from α-peptide geometries, β-amino acids greatly expand the possible chemistries and physical properties available to polyamide foldamers. Complete in silico support for designing new molecules incorporating non-natural amino acids typically requires representing their side-chain conformations as sets of discrete rotamers for model refinement and sequence optimization. Such rotamer libraries are key components of several state-of-the-art design frameworks. Here we report the development, incorporation in to the Rosetta macromolecular modeling suite, and validation of rotamer libraries for β3-amino acids.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

“…30,[38][39][40][41] One approach to foldamer prediction and design has been to use ab initio modeling to construct rotamer libraries of residue types that can be used with existing tools for protein design such as Rosetta. 38,[42][43][44] While this enables fast searching of sequence and structure space, the main drawback is the difficulty of parameterization. The rotamers of each new residue must be calculated separately, and it is challenging to empirically parameterize inter-residue interactions without a large number of known structures.…”

Reverse Turn Foldamers: An Expanded β-Turn Motif Reinforced by Double Hydrogen Bonds

“…Foldamers are unnatural oligomers with their basic residues derived from higher homologues of α-amino acids such as β-, γ-, and δ-amino acids, aromatic amino acids, and other unnatural monomers or hybrids of α-amino acid and unnatural residues, which adopt well-defined conformations. The majority of known foldamers adopt helical conformations, whereas folding of unnatural oligomers into sheets and turns is less common in spite of the ubiquitous occurrence of such secondary structures in proteins.…”

Synthesis and characterization of new 5,5′-dimethyl- and 5,5′-diphenylhydantoin-conjugated hemorphin derivatives designed as potential anticonvulsant agents

“…Moreover, the amino acid Pro is often found in b-folded sheets because it contains a tetrahydropyrrole ring and is not compatible with helix formation. 58,60 In the two short-chain peptides Dm-4 and Ph-4, all characteristic bands showing a certain type of secondary structure are observed. However, this could not be completely proved because of the small length of the peptide chain.…”

“…In the region 1678-1722 cm À1 , there is a high-intensity peak of n CQO (amide I), which is usually observed during conformation in a b-structure. 58,60 The appearance of a high absorption maximum at 1511-1528 cm À1 (d NH , amide II) suggests the presence of a b-curve or b-sheet structure 59 a especially for peptides Dm-5, Ph-5, Dm-7 and Ph-7 (Fig. 2).…”