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

The Schellman motif is a widely observed, helix terminating structural motif in proteins, which is achieved by the adoption of a left-handed helical (at) 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 3(10)-helix terminated by a Schellman motif with Aib(6) adopting an alpha(L) - conformation. The crystals are in the space group P2(1) with a=9.958(3) Angstrom, b=20.447(3)A, c=11.723 (2) Angstrom, beta=99.74(2)degrees, and Z = 2. The final R-1 and wR(2) values are 7.2% and 18.9%, respectively, for 1731 observed reflections [I greater than or equal to 2 sigma(1)]. 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 alpha(L) terminated helical peptides in crystals suggests that the medium range (CiH)-H-alpha----Ni+3H [d(alpha N)(i,i+3)] and (CiH)-H-alpha----Ni+4H [d(alpha)(i,i+4)] interproton distances are indeed characteristic of the Schellman motif. NMR studies in CDCl3 establish retention of the 3(10)-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.