A systematic study of fundamentals in α-helical coiled coil mimicry by alternating sequences of ß- and γ-amino acids.

Aimed at understanding the crucially important structural features for the integrity of α-helical mimicry by ßγ-sequences, an α-amino acid sequence in a native peptide was substituted by differently arranged ßγ-sequences. The self- and hetero-assembly of a series of αßγ-chimeric sequences based on a 33-residue GCN4-derived peptide was investigated by means of molecular dynamics, circular dichroism, and a disulfide exchange assay. Despite the native-like behavior of ßγ alternating sequences such as retention of α-helix dipole and the formation of 13-membered α-helix turns, the αßγ-chimeras with different ßγ substitution patterns do not equally mimic the structural behavior of the native parent peptide in solution. The preservation of the key residue contacts such as van der Waals interactions and intrahelical H-bonding, which can be met only by particular substitution patterns, thermodynamically favor the adoption of coiled coil folding motif. In this study, we show how successfully the destabilizing structural consequences of α â†’ ßγ modification can be harnessed by reducing the solvent-exposed hydrophobic surface area and placing of suitably long and bulky helix-forming side chains at the hydrophobic core. The pairing of αßγ-chimeric sequences with the native wild-type are thermodynamically allowed in the case of ideal arrangement of ß- and γ-residues. This indicates a similarity in local side chain packing of ß- and γ-amino acids at the helical interface of αßγ-chimeras and the native α-peptide. Consequently, the backbone extended residues are able to participate in classical "knob-into-hole" packing with native α-peptide.

Synthetic strategies to alpha-trifluoromethyl and alpha-difluoromethyl substituted alpha-amino acids.

The combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach to the design of biologically active compounds including peptides with improved pharmacological parameters. Therefore, the development of routine synthetic methods which enable the effective and selective introduction of fluorine into the desired amino acids from readily available starting materials is of significant synthetic importance. The scope of this critical review is to summarize the most frequently employed strategies for the synthesis of alpha-difluoromethyl and alpha-trifluoromethyl substituted alpha-amino acids (114 references).