Prema G. Vasudev

Structural chemistry of peptides containing backbone expanded amino acid residues: conformational features of β, γ, and hybrid peptides.

6. ω Amino Acids in Hairpins 672 6.1. Insertion into Turn Segments 672 6.2. Extended Strands 673 7. Conformational Representations 673 7.1. Conformationally Constrained Residues 675 8. Conformational Variability and Biological Activity 677 8.1. Conformational Variability in Solution 677 8.2. Biological Activity of Synthetic Peptides 678 9. Revisiting Hydrogen-Bonded Rings and Polypeptide Helices 678

Gabapentin: a stereochemically constrained gamma amino acid residue in hybrid peptide design.

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino acids, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino acids with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino acid residue that contains a cyclohexyl ring at the C(beta) carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C(7) and C(9) hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alphagamma sequences, distinct C(12) hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Expanding the Peptide beta-Turn in alpha gamma Hybrid Sequences: 12 Atom Hydrogen Bonded Helical and Hairpin Turns

Hybrid peptide segments containing contiguous alpha and gamma amino acid residues can form C(12) hydrogen bonded turns which may be considered as backbone expanded analogues of C(10) (beta-turns) found in alphaalpha segments. Exploration of the regular hydrogen bonded conformations accessible for hybrid alphagamma sequences is facilitated by the use of a stereochemically constrained gamma amino acid residue gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn), in which the two torsion angles about C(gamma)-C(beta) (theta(1)) and C(beta)-C(alpha) (theta(2)) are predominantly restricted to gauche conformations. The crystal structures of the octapeptides Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (1) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (2) reveal two distinct conformations for the Aib-Gpn segment. Peptide 1 forms a continuous helix over the Aib(2)-Aib(6) segment, while the peptide 2 forms a beta-hairpin structure stabilized by four cross-strand hydrogen bonds with the Aib-Gpn segment forming a nonhelical C(12) turn. The robustness of the helix in peptide 1 in solution is demonstrated by NMR methods. Peptide 2 is conformationally fragile in solution with evidence of beta-hairpin conformations being obtained in methanol. Theoretical calculations permit delineation of the various C(12) hydrogen bonded structures which are energetically feasible in alphagamma and gammaalpha sequences.

Hybrid αγ Polypeptides: Structural Characterization of a C12/C10 Helix with Alternating Hydrogen-Bond Polarity†

The insertion of the higher homologues of the \alpha-amino acids, specifically \beta, \gamma, and \delta residues, into a peptide sequences results in hybrid structures with novel hydrogen-bonding possibilities.[1] Research in this area of hybrid polypeptides has been stimulated by the observation of novel helical structures in \beta oligopeptides in which the hydrogen-bond polarities are reversed. For example, the 12 helix

Multiple Conformational States in Crystals and in Solution in \alpha\gamma Hybrid Peptides. Fragility of the

(2.5_{12}

C_{12}

or

Helix in Short Sequences

2.5_1-P)

Asparagine and glutamine differ in their propensities to form specific side chain-backbone hydrogen bonded motifs in proteins

in a

Conformations of β‐amino acid residues in peptides: X‐ray diffraction studies of peptides containing the achiral residue 1‐aminocyclohexaneacetic acid, β3,3Ac6c

(\beta)_n

Crystal structures of a new polymorphic form of gabapentin monohydrate and the e and z isomers of 4-tertiarybutylgabapentin.

sequence maintains the same directionality