Induction of One-Handed Helical Screw Sense in Achiral Peptide through the Domino Effect Based on Interacting Its N-Terminal Amino Group with Chiral Carboxylic Acid

Abstract

A helical chain being the most common secondary structure in biopolymers prefers one-handed (left-or right-handed) screw sense, when chiral moieties are incorporated into the main or side chain through the covalent bond. We here report that an achiral helical peptide prefers the one-handed helical screw sense by noncovalent interaction of its N-terminal amino group with a chiral carboxylic acid. Little is known about such phenomena in peptide systems typical of biopolymers, although it has been reported that synthetic helical polymers bearing carboxyl or amino groups in the repeating units induce the one-handed screw sense by addition of chiral small amines or acids to interact on their polymer side or main chains. 1 In our system, the acid-base interaction occurring in the N-terminal position of the peptide chain will lead to the predominance of one-handed screw sense of the entire peptide chain, namely through domino effect. For our purpose, the following N-deprotected nonapeptide 1 consisting of nonprotein amino acids [R-aminoisobutyric acid (Aib) and R, -dehydrophenylalanine (∆ Z Phe)] was synthesized. 2 Peptide 1 can be expected to generate two "enantiomeric" (leftand right-handed) helices, since Aib and ∆ Z Phe residues are achiral ones and strong inducers for forming a 3 10 -helix. 3 Actually, a helical conformation was evidenced by 1 H NMR spectroscopy on peptide 1 in CDCl 3 . In the NOESY experiment, marked crosspeaks were observed for the N i H-N i+1 H resonances in the segment of Aib(3) to Aib(9), 2 indicating that peptide 1 forms a 3 10 -or R-helix. 4 The solvent dependence on amide NH chemical shifts in CDCl 3 /(CD 3 ) 2 SO mixtures revealed that six NH resonances of ∆ Z Phe(4) to Aib(9) residues are shielded from solvent due to intramolecular hydrogen bonding, 2 of which the pattern corresponds to a 3 10 -helix. The helical conformation was also supported by the amide I absorption bands of its FT-IR spectrum in chloroform: 1660 and 1627 cm -1 , which can be assigned to saturated amino acid and ∆ Z Phe residues in a helical segment, respectively. 5 Furthermore, energy minimization of peptide 1 by the semiempirical molecular orbital method 6 gave a 3 10 -helical conformation ( Figure 1) characterized by 〈φ〉 ) (41.1°, 〈ψ〉 ) (37.6°, and 〈ω〉 ) 180.0°for average values of ∆ Z Phe(2) to ∆ ZPhe(8) residues, and the main-chain energy contour map was severely restricted into right-and left-handed helical regions (φ ) (60 to (40°, ψ ) (60 to (30°). 2 Therefore, peptide 1 having a strong helix-forming tendency forms a 3 10 -helical conformation in chloroform. 7 Peptide 1 could not show any CD signals due to the absence of chiral residues, thus taking both left-and right-handed helices with the same content in an equilibrium state (Figure 2, dotted line). However, intense split CD signals were induced around 282 nm assignable to ∆ Z Phe residues by the addition of enantiomerically pure Boc-L-Pro-OH (Boc ) t-butoxycarbonyl), as shown in Figure 2. The mirror image was obtained by the addition of Boc-D-Pro-OH, th...

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

“…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.…”

Synthesis and structure determination of helical polymers

“…As a consequence, they consist of interconvertible right-and lefthanded helical segments separated by rarely occurring helical reversals, as demonstrated by Green et al, 6,20,21 so that a preferred-handed helical conformation can be induced in the presence of a small amount of chiral residues at the pendant 6 or terminal ends 22,23 or a noncovalently interacting stimulant, 24 with their helical senses being determined under thermodynamic control. Either static or dynamic helical polymers with an excess one-handedness, such as poly(quinoxaline-2,3-diyl)s (4), 25,26 polyguanidines (5), 27,28 poly(phenyl isocyanide)s (6) 29,30 and polyacetylenes (7), [8][9][10][11][12][31][32][33][34] have also been prepared by the polymerization of analogous monomers bearing different chiral or achiral substituents, that is, the boundary between static and dynamic helical conformations is totally dependent on the helix inversion barrier.…”

Effect of the ΔPhe residue configuration on a didehydropeptides conformation: A combined CD and NMR study

“…The peptides contain a ∆Phe residue which gives a large CD band in that region, at about 280 nm, which is very sensitive to a dehydropeptide conformation. 18,19,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Thus, this residue is a very good conformational probe in the studies on dehydropeptides. Moreover, Z-p-NA and E-p-NA contain the p-NA group which has been also found to be a useful tool in the conformational studies on peptides.…”