The hydrophobic Arg-Phe and Phe-Met side chain interactions stabilize the α-helix by -0.29 and -0.59 kcal/mol, respectively, when placed i, i + 4 in an alanine-based peptide. When both interactions are present simultaneously, however, they stabilize the helix by an additional -0.75 kcal/mol, nearly as much as the sum of its parts. We attribute this coupling to a shared rotamer preference, as the central Phe is t in both bonds. The energetic cost of restricting the Phe residue into a t conformation is only paid once in the triplet, rather than twice when the interactions are separate. Coupling is thus demonstrated to have large effects on protein stability. Copyright © 2005 American Chemical Society.