Mechanism for the Noncovalent Chiral Domino Effect:  New Paradigm for the Chiral Role of the N-Terminal Segment in a 3₁₀-Helix

Abstract

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.

Chiral interaction in Gly‐capped N‐terminal motif of 310‐helix and domino‐type induction in helix sense

“…14,15,[17][18][19][24][25][26][27][28][29][30] 14. (S)-5 was also purchased, which is shown later (Scheme 2).…”

“…[36][37][38] A right-handed 3 10 -helix of peptide 2, already obtained by energy minimization, 14 was basically used as the starting conformation of peptide 1. A keyword of ''MMOK'' 37,38 for correction of the amide-bond barrier was specified to the minimization.…”

“…The terminal-triggered control of helical sense is figuratively termed the noncovalent chiral domino effect (NCDE). [14][15][16][17][18][19][20][21] The effect implies that chiral recognition and modulation of structural asymmetry occur at the N-terminus of a peptide helical chain.…”

“…[14][15][16]20,21 The combination of such an achiral sequence with natural L-residue(s) at the internal or C-terminal position also has been employed for the NCDE experiments. [17][18][19] The N-terminus, though significant in the binding site, has been designed by nonstandard protein amino acids such as -aminoisobutyric acid (Aib), 15,17,18 -alanine (-Ala), 14,[19][20][21] and N-methyl glycine. 16 Furthermore, the detailed mechanism for the NCDE has not been experimentally evidenced in helical sequences designed with onlyamino acids, whereas such sequences might undergo a similar mechanism demonstrated in the N--Alaterminal peptide.…”

“…16 Furthermore, the detailed mechanism for the NCDE has not been experimentally evidenced in helical sequences designed with onlyamino acids, whereas such sequences might undergo a similar mechanism demonstrated in the N--Alaterminal peptide. 14 Under such circumstances, we here have picked up achiral sequence 1 (see Scheme 1) possessing one glycine (Gly) at its N-terminus. The present study aims to clarify whether the domino-type chiral interaction occurs in the sequence capped by Gly residue as a natural protein residue.…”