Influence of hydrophobic interactions on the conformational adaptability of the beta-Ala residue

The chemical synthesis and X-ray crystal structure analysis of a model pept ide incorporating a conformationally flexible beta -Ala residue: Boc-beta - Ala-Pda, 1 (C23H46N2O3: molecular weight = 398.62) have been described. The peptide crystallized in the crystal system triclinic with space group P2(1 ): a=5.116(3) Angstrom, b=5.6770(10) Angstrom, c=21.744(5) Angstrom; alpha =87.45, beta =86.87, gamma =90.0; Z=1. An attractive feature of the crystal molecular structure of 1 is the induction of a reasonably extended backbon e conformation of the beta -Ala moiety, i.e. the torsion angles phi approxi mate to -115 degrees, mu approximate to 173 degrees and psi approximate to 122 degrees, correspond to skew, trans and skew(+) conformation, respective ly, by an unbranched hydrophobic alkyl chain, Pda, which prefers an all-ant i orientation (theta (1) approximate to -153 degrees, theta (2) approximate to... theta (14) approximate to 178 degrees). The observation is remarkabl e because, systematic conformational investigations of short linear beta -A la peptides of the type Boc-beta -Ala-Xaa-OCH3 (Xaa=Aib or ACC(6)) have sho wn that the chemical and stereochemical characters of the neighboring moiet ies may be critical in dictating the overall folded and/or unfolded conform ational features of the beta -Ala residue. The overall conformation of 1 is typical of a 'bar'. It appears convincing that, in addition to a number of hydrophobic contacts between the parallel arranged molecules, an array of conventional N-H...O=C intermolecular H-bonding interactions stabilize the crystal molecular structure. Moreover, the resulting 14-membered pseudo-rin g motif, generated by the amide-amide interactions between the adjacent mol ecules, is completely devoid of nonconventional C-H...O interaction. The po tentials of the conformational adaptation of the B-Ala residue, to influenc e and stabilize different structural characteristics have been highlighted.