Characterization of helix terminating schellman motifs in peptides. Crystal structure and nuclear overhauser effect analysis of a synthetic heptapeptide helix

Abstract

The Schellman motif is a widely observed, helix terminating structural motif in proteins, which is achieved by the adoption of a left-handed helical (α_L) conformation by a C-terminus residue. The resulting hydrogen bonding pattern involves an intramolecular 6 → 1 interaction. This helix terminating motif is readily mimicked in synthetic helical peptides by placing an achiral residue at the penultimate position of the helix. The crystal structure of the heptapeptide Boc-Leu-Aib-Val-Gly-Leu-Aib-Val-OMe (1) reveals a 3₁₀-helix terminated by a Schellman motif with Aib(6) adopting an α_L - conformation. The crystals are in the space group P2₁ with a = 9.958(3)Å, b = 20.447(3)Å, c = 11.723 (2)Å, β = 99.74(2)°, and Z = 2. The final R₁ and wR₂ values are 7.2% and 18.9%, respectively, for 1731 observed reflections [I ≥ 2σ(I)]. A 6 →1 hydrogen bond between Aib(2)CO----Val(7)NH and a 5→2 hydrogen bond between Val(3)CO----Aib(6)NH are observed. An analysis of several α_L terminated helical peptides in crystals suggests that the medium range C_i^αH----N_i+3H [d_αN(i,i+3)] and C_i^αH----N_i+4H [d_αNN(i,i+4)] interproton distances are indeed characteristic of the Schellman motif. NMR studies in CDCl₃ establish retention of the 3₁₀-helical conformation with key NOEs demonstrating the persistence of the conformation determined in crystals. The present study demonstrates the identification of the Schellman motif in solution in a synthetic helical peptide.