TESTS FOR HELIX-STABILIZING INTERACTIONS BETWEEN VARIOUS NONPOLAR SIDE-CHAINS IN ALANINE-BASED PEPTIDES

Straight-chain, non-natural, nonpolar amino acids norleucine, norvaline, and alpha-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 alpha-helix strongly favors the interaction between 2 nonpolar residues to stabilize an isolated alpha-helix.