Tests for helix‐stabilizing interactions between various nonpolar side chains in alanine‐based peptides

Straight‐chain, non‐natural, nonpolar amino acids norleucine, norvaline, and α‐amino‐n‐butyric acid at various spacings do not interact with themselves to stabilize helix formation in alanine‐based peptides, but do interact with a Tyr spaced i, i + 4 to stabilize alanine helices, similar to the helix‐stabilizing i, i + 4 Tyr‐Leu and Tyr‐Val interactions reported earlier (Padmanabhan S, Baldwin RL, 1994, J Mol Biol 241:706–713). Leu spaced i, i + 4 from another Leu is measurably helix‐stabilizing relative to the corresponding i, i + 3 pair, but less so than for i, i + 4 Val‐Leu, Ile‐Leu, or Phe‐Leu pairs (relative to the corresponding i, i + 3 pairs) when Leu is C‐terminal to the other nonpolar amino acid. Our results indicate that limited side‐chain flexibility in an α‐helix strongly favors the interaction between 2 nonpolar residues to stabilize an isolated α‐helix.

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