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Effect of Differential Geminal Substitution of γ Amino Acid Residues at the (i + 2) Position of αγ Turn Segments on the Conformation of Template β-Hairpin Peptides.

Swapna DebnathSuvankar GhoshGopal PanditPriyadarshi SatpatiSunanda Chatterjee
Published in: The Journal of organic chemistry (2021)
The effect of insertion of three geminally dimethyl substituted γ amino acid residues [γ2,2 (4-amino-2,2-dimethylbutanoic acid), γ3,3 (4-amino-3,3-dimethylbutanoic acid), and γ4,4 (4-amino-4,4-dimethylbutanoic acid)] at the (i + 2) position of a two-residue αγ C12 turn segment in a model octapeptide sequence Leu-Phe-Val-Aib-Xxx-Leu-Phe-Val (where Xxx = γ amino acid residues) has been investigated in this study. Solution conformational studies (NMR, CD, and IR) and ab initio calculations indicated that γ3,3 and γ4,4 residues were well accommodated in the β-hairpin nucleating αγ C12 turns, which gave rise to well-registered hairpins, in contrast to γ2,2, which was unable to form a tight C12 β-hairpin nucleating turn and promote a well-registered β-hairpin. Geminal disubstitution at the Cα carbon in γ2,2 led to unfavorable steric contacts, disabling its accommodation in the αγ C12 hairpin nucleating turn unlike the γ3,3 and γ4,4 residues. Geminal substitutions at different carbons along the backbone constrained backbone torsion angles for the three γ amino acid residues differently, generating diverse conformational preferences in them. Folded hairpins were energetically more stable (∼8 to 9 kcal/mol) than the unfolded peptides. Conformational preference of the peptides was independent of the N-terminal protecting group. Such fundamental understanding will instrumentalize the future directed design of foldamers.
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