Mechanism for the noncovalent chiral domino effect: new paradigm for the chiral role of the N-terminal segment in a 3(10)-helix.
Recently, novel chiral interactions on 3(10)-helical peptides, of which the helicity is controlled by external chiral stimulus operating on the N-terminus, were proposed as a "noncovalent chiral domino effect (NCDE)" (Inai, Y.; et al. J. Am. Chem. Soc. 2000, 122, 11731. Inai, Y.; et al. J. Am. Chem. Soc. 2002, 124, 2466). The present study clarifies the mechanism for generating the NCDE. For this purpose, achiral nonapeptide (1), H-beta-Ala-(Delta(Z)Phe-Aib)(4)-OMe [Delta(Z)Phe = (Z)-didehydrophenylalanine, Aib = alpha-aminoisobutyric acid], was synthesized. Peptide 1 alone adopts a 3(10)-helical conformation in chloroform. On the basis of the induced CD signals of peptide 1 with chiral additives, chiral acid enabling the predominant formation of a one-handed helix was shown to need at least both carboxyl and urethane groups; that is, Boc-l-amino acid (Boc = tert-butoxycarbonyl) strongly induces a right-handed helix. NMR studies (NH resonance variations, low-temperature measurement, and NOESY) were performed for a CDCl(3) solution of peptide 1 and chiral additive, supporting the view that the N-terminal H-beta-Ala-Delta(Z)Phe-Aib, including the two free amide NH's, captures effectively a Boc-amino acid molecule through three-point interactions. The H-beta-Ala's amino group binds to the carboxyl group to form a salt bridge, while the Aib(3) NH is hydrogen-bonded to either oxygen of the carboxylate group. Subsequently, the free Delta(Z)Phe(2) NH forms a hydrogen bond to the urethane carbonyl oxygen. A semiempirical molecular orbital computation explicitly demonstrated that the dynamic looping complexation is energetically permitted and that the N-terminal segment of a right-handed 3(10)-helix binds more favorably to a Boc-l-amino acid than to the corresponding d-species. In conclusion, the N-terminal segment of a 3(10)-helix, ubiquitous in natural proteins and peptides, possesses the potency of chiral recognition in the backbone itself, furthermore enabling the conversion of the terminally acquired chiral sign and power into a dynamic control of the original helicity and helical stability.
Inai
Yoshihito
Y
Department of Environmental Technology and Urban Planning, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan. inai@mse.nitech.ac.jp
Ousaka
Naoki
N
Okabe
Takahiro
T
D000621:Aminoisobutyric Acids / Q000737:chemistry; D003080:Cold Temperature; D005563:Formic Acid Esters / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives; D017433:Protein Structure, Secondary; D012996:Solutions; D013237:Stereoisomerism; D013816:Thermodynamics
D000621:Aminoisobutyric Acids; D005563:Formic Acid Esters; D009842:Oligopeptides; D012996:Solutions; C000345:t-butyloxycarbonyl group; D010649:Phenylalanine