Ambidexterity and Left-Handedness Induced by Geminally Disubstituted γ Amino Acid Residues in Chiral 3 10 Helices.

Chirality is an omnipresent feature in nature's architecture starting from simple molecules like amino acids to complex higher-order structures viz. proteins, DNA, and RNA. The L configuration of proteinogenic amino acids gives rise to right-handed helices. Ambidexterity is as rare in organisms as in molecules. There are only a few reports of ambidexterity in single-peptide molecules composed of either mixed L and D or achiral residues. Here, we report, for the first time, the ambidextrous and left-handed helical conformations in the chiral nonapeptides P1-P3 (Boc-LUVUγ x , x ULUV-OMe where U = Aib, x , x = 2,2/3,3/4,4), containing chiral L α amino acid residues, in addition to the usually observed right-handed helical conformation. The centrally located achiral γ residue, capable of adopting both left and right-handed helical conformations, induces its handedness on the neighboring chiral and achiral residues, leading to the observation of both left and right-handed helices in P2 and P3 . The presence of a single water molecule proximal to the γ residue induces the reversal of helix handedness by forming distinct and stable water-mediated hydrogen bonds. This gives rise to ambidextrous helices as major conformers in P1 and P2 . The absence of the observation of ambidexterity in P3 might be due to the inability of γ 4,4 in the recruitment of a water molecule. Experiments (NMR, X-ray, and CD) and density functional theory (DFT) calculations suggest that the position of geminal disubstitution is crucial for determining the population of the amenable helical conformations (ambidextrous, left and right-handed) in these chiral peptides.