Unfolding of an α‐helix in peptide crystals by solvation: Conformational fragility in a heptapeptide

Abstract

The structure of the peptide Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe has been determined in crystals obtained from a dimethylsulfoxide-isopropanol mixture. Crystal parameters are as follows: C38H69N7O10.H2O.2C3H7OH, space group P2(1), a = 10.350 (2) A b = 26.084 (4) A, c = 10.395 (2) A, beta = 96.87 (12), Z = 2, R = 8.7% for 2686 reflections observed > 3.0 sigma (F). A single 5-->1 hydrogen bond is observed at the N-terminus, while two 4-->1 hydrogen bonds characteristic of a 3(10)-helix are seen in the central segment. The C-terminus residues, Ala(6) and Leu(7) are extended, while Val(5) is considerably distorted from a helical conformation. Two isopropanol molecules make hydrogen bonds to the C-terminal segment, while a water molecule interacts with the N-terminus. The structure is in contrast to that obtained for the same peptide in crystals from methanol-water [I. L. Karle, J. L. Flippen-Anderson, K. Uma, and P. Balaram (1990) Proteins: Structure, Function and Genetics, Vol. 7, pp. 62-73] in which two independent molecules reveal an almost perfect alpha-helix and a helix penetrated by a water molecule. A comparison of the three structures provides a snapshot of the progressive effects of solvation leading to helix unwinding. The fragility of the heptapeptide helix in solution is demonstrated by nmr studies in CDCl3 and (CD3)2SO. A helical conformation is supported in the apolar solvent CDCl3, whereas almost complete unfolding is observed in the strongly solvating medium (CD3)2SO.