Side‐chain interactions in the C‐peptide helix: Phe 8 ⃛ His 12+

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Abstract
Previous studies have demonstrated that His 12 plays a major role in the pH‐dependent stability of the helix formed by the isolated C‐peptide (residues 1–13 of ribonuclease A). Here, amino acid replacement experiments show that His 12+ stabilizes the C‐peptide helix chiefly by interacting with Phe 8. The Phe 8 ⃛ His 12+ ring interaction is specific for the protonated form of His 12 (His 12+) and the interaction is not screened significantly by NaCl, unlike the charged group ⃛ helix dipole interactions studied earlier in C‐peptide. Analogs of C‐peptide that are unable to form the Phe 8 ⃛ His 12+ interaction show large increases in helix content for Phe → Ala and His → Ala. Therefore, the helical tendencies of the individual residues Phe, His, and Ala are important in determining the result of a replacement experiment. Since the side chains of Phe 8 and His 12 probably interact within the N‐terminal helix of ribonuclease A, the existence of the Phe 8 ⃛ His 12+ interaction in the isolated C‐peptide helix adds to the evidence that the C‐peptide helix is an autonomous folding unit.