Alpha,gamma- and beta,gamma-hybrid peptides, which are composed of two different homologous amino acid constituents in alternate order, are suggested as novel classes of peptide foldamers. On the basis of a systematic conformational search employing the methods of ab initio MO theory, the possibilities for the formation of periodic secondary structures in these systems are described. The conformational analysis provides a great number of helix conformers widely differing in energy, which can be arranged into three groups: (i) helices with all hydrogen bonds formed in forward direction along the sequence, (ii) helices with all hydrogen bonds in backward direction, and (iii) helices with alternate hydrogen-bond directions (mixed or beta-helices). Most stable are representatives of beta-helices, but their stability decreases considerably in more polar environments in comparison to helix conformers from the other two classes. There is a great similarity between the overall topology of the most stable hybrid peptide helices and typical helices of peptides which are exclusively composed of a single type of homologous amino acids. Thus, the helices of the beta,gamma-hybrid peptides mimic perfectly those of the native alpha-peptides as, for instance, the well-known alpha-helix, whereas the most stable helix conformers of alpha,gamma-hybrid peptides correspond well to the overall structure of beta-peptide helices. The two suggested novel hybrid peptide classes expand considerably the pool of peptide foldamers and may be promising tools in peptide design and in material sciences.

The conformation of oligomers of beta-amino acids of the general type Ac-[beta-Xaa]n-NHMe (beta-Xaa = beta-Ala, beta-Aib, and beta-Abu; n = 1-4) was systematically examined at different levels of ab initio molecular orbital theory (HF/6-31G*, HF/3-21G). The solvent influence was considered employing two quantum-mechanical self-consistent reaction field models. The results show a wide variety of possibilities for the formation of characteristic elements of secondary structure in beta-peptides. Most of them can be derived from the monomer units of blocked beta-peptides with n = 1. The stability and geometries of the beta-peptide structures are considerably influenced by the side-chain positions, by the configurations at the C alpha- and C beta-atoms of the beta-amino acid constituents, and especially by environmental effects. Structure peculiarities of beta-peptides, in particular those of various helix alternatives, are discussed in relation to typical elements of secondary structure in alpha-peptides.

You may now exchange rings! “Mixed helices” along a peptide sequence, in which rings of different sizes are held together by hydrogen bonds in alternating directions (see picture), prove to be a general folding principle in homologous α‐, β‐, γ‐, and δ‐peptides.

A complete overview of all possible periodic structures with characteristic H‐bonding patterns is provided for oligomers composed of γ‐amino acids (γ‐peptides) and their vinylogues by a systematic conformational search on hexamer model compounds employing ab initio MO theory at various levels of approximation (HF/6‐31G*, DFT/B3LYP/6‐31G*, SCRF/HF/6‐31G*, PCM//HF/6‐31G*). A wide variety of structures with definite backbone conformations and H‐bonds formed in forward and backward directions along the sequence was found in this class of foldamers. All formally conceivable H‐bonded pseudocycles between 7‐ and 24‐membered rings are predicted in the periodic hexamer structures, which are mostly helices. The backbone elongation in comparison to α‐ and β‐peptides allows several possibilities to realize identical H‐bonding patterns. In good agreement with experimental data, helical structures with 14‐ and 9‐membered pseudocycles are most stable. It is shown that the introduction of an (E)‐double bond into the backbone of the γ‐amino acid constituents, which leads to vinylogous γ‐amino acids, supports the folding into helices with larger H‐bonded pseudocycles in the resulting vinylogous γ‐peptides. Due to the considerable potential for secondary‐structure formation, γ‐peptides and their vinylogues might be useful tools in peptide and protein design and even in material sciences.

Peptoids of alpha- and beta-peptides (alpha- and beta-peptoids) can be obtained by shifting the amino acid side chains from the backbone carbon atoms of the monomer constituents to the peptide nitrogen atoms. They are, therefore, N-substituted poly-glycines and poly-beta-alanines, respectively. Due to the substituted nitrogen atoms, the ability for hydrogen bond formation between peptide bonds gets lost. It may be very interesting to see whether such non-natural oligomers could be regarded as foldamers, which fold into definite backbone conformers. In this paper, we provide a complete overview on helix formation in alpha- and beta-peptoids on the basis of systematic theoretical conformational analyses employing the methods of ab initio molecular orbital (MO) theory. It can be shown that the alpha- and beta-peptoid structures form helical structures with both trans and cis peptide bonds despite the missing hydrogen bonds. Obviously, the conformational properties of the backbone are more important for folding than the possibility of hydrogen bonding. There are close relationships between the helices of alpha-peptoids and poly-glycine and poly-proline helices of alpha-peptides, whereas the helices of beta-peptoids correspond to the well-known helical structures of beta-peptides as, for instance, the 3(1)-helix of beta-peptides with 14-membered hydrogen-bonded rings. Thus, alpha- and beta-peptoids enrich the field of foldamers and may be used as useful tools in peptide and protein design.

This study provides a complete overview on all possible helical- folding patterns, their stabilities, and their detailed molecular structure in the novel foldamer class of alpha,beta-hybrid peptides on the basis of ab initio molecular orbital (MO) theory. The results indicate a considerable intrinsic potential of backbone folding. As found for other peptide foldamers, representatives of mixed or beta-helices are most stable in more apolar media, whereas polar environments favor the helices with the hydrogen bonds pointing in only one direction. The theoretical results confirm the hydrogen-bonding patterns found in the first experimental studies on these hybrid peptides. Selecting special backbone substitution patterns, the secondary structure potential of the alpha,beta-hybrid peptides could be of great importance for a rational peptide and protein design.

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Dedicated to Prof. Dr. Peter Welzel on the occasion of his 65th birthday A systematic conformational analysis on blocked b-amino acids as constituents of b-peptides by ab initio MO theory reveals that the conformer pool of b-peptide monomers is essentially determined by the conformation of simple submonomer fragments. The influence of single and multiple substitutions at the C(a) and C(b) backbone atoms on the intrinsic folding properties of the monomers was estimated both in the singlemolecule approximation and in a polar solvent continuum, applying a quantum-chemical SCRF model. Substitution at C(b) has a higher impact on the b-amino acid conformation than a substitution at C(a). It can be shown that the conformations of important periodic secondary structures in b-peptides belong to the conformer pool of the monomers, even for those secondary-structure elements where H-bond formation appears only in longer sequences. Rules for design of special secondary-structure types by selection of an actual substituent pattern in the b-amino acid constituents have been derived within the monomer approach.1. Introduction. ± In recent years, oligomers of b-amino acids, called b-peptides, have gained much attraction because of their ability to form well-ordered secondary structures [1 ± 6], e.g., b-strand-like conformers [7 ± 9], reverse turns [10 ± 14], and, in particular, helices with differing H-bonding patterns [15 ± 34]. Some representatives are stable against proteases [35 ± 37] and can be translocated across the cell membrane [38] [39], which makes b-peptides possible candidates for pharmacological applications [40 ± 49]. In comparison to a-amino acid constituents, b-amino acids offer a much greater number of different substituent patterns, which should influence the secondarystructure formation in peptide sequences. Therefore, it might be useful to look for the intrinsic folding properties in b-peptide models with substituents in various positions.It is a tempting approach to derive the characteristic secondary structures in peptide sequences from the conformational properties of the monomer constituents (monomer approach). Numerous systematic conformational analyses on blocked a-amino acids and unnatural amino acids have been reported [50 ± 74]. These theoretical studies, employing molecular-orbital (MO) theory and empirical force fields, indicate that most of the typical secondary structures found in peptides and proteins already belong to the conformer pool of the monomers. This concerns even those secondary-structure elements that are characterized by H-bond formation between amino acid residues that are more or less distant in the sequence. Obviously, H-bonds may significantly influence the stability relationships between competing folding alternatives, but they are not the driving force for the formation of the corresponding conformers themselves.