Stabilizing nonpolar/polar side-chain interactions in the alpha-helix

A simplistic, yet often used, view of protein stability is that amino acids attract other amino acids with similar polarity, whereas nonpolar and pola r side chains repel. Here we show that nonpolar/polar interactions, namely Val or Ile bonding to Lys or Arg in a-helices, can in fact be stabilizing. Residues spaced i, i + 4 in a-helices are on the same face of the helix, wi th potential to favorably interact and stabilize the structure. We observe that the nonpolar/polar pairs Ile-Lys, Ile-Arg, and Val-Lys occur in protei n helices more often than expected when spaced i, i + 4. Partially helical peptides containing pairs of nonpolar/polar residues were synthesized. Cont rols with i, i + 5 spacing have the residues on opposite faces of the helix and are less helical than the test peptides with the i, i + 4 interactions . Experimental circular dichroism. results were analyzed with helix-coil th eory to calculate the free energy for the interactions. All three stabilize the helix with AG between -0.14 and -0.32 kcal . mol(-1). The interactions are hydrophobic with contacts between Val or Ile and the alkyl groups in A rg or Lys. Side chains such as Lys and Arg can thus interact favorably with both polar and nonpolar residues. (C) 2001 Wiley-Liss, Inc.