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

Aimed at understanding the crucially important structural features for the integrity of alpha-helical mimicry by beta gamma-sequences, an alpha-amino acid sequence in a native peptide was substituted by differently arranged beta gamma-sequences. The self- and hetero-assembly of a series of alpha beta gamma-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 beta gamma alternating sequences such as retention of alpha-helix dipole and the formation of 13-membered alpha-helix turns, the alpha beta gamma-chimeras with different beta gamma 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 alpha -> beta gamma 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 alpha beta gamma-chimeric sequences with the native wild-type are thermodynamically allowed in the case of ideal arrangement of beta- and gamma-residues. This indicates a similarity in local side chain packing of beta- and gamma-amino acids at the helical interface of alpha beta gamma-chimeras and the native alpha-peptide. Consequently, the backbone extended residues are able to participate in classical knob-into-hole packing with native alpha-peptide.