Induction of a heterochiral helix through the covalent chiral domino effect originating in the "Schellman motif"

Article abstract of DOI:10.1021/ja063873n

We report unique phenomena where the transition from a homochiral helix to a heterochiral helix occurs by increasing the chain length of the l-sequence. Peptides composed of the l-Leu sequences with different lengths and the achiral nona-sequence at the C

Full text of DOI:10.1021/ja063873n

Published on Web 10/27/2006
Induction of a Heterochiral Helix through the Covalent Chiral Domino Effect
Originating in the “Schellman Motif”
Naoki Ousaka and Yoshihito Inai*
Department of EnVironmental Technology and Urban Planning, Shikumi College, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
Received June 2, 2006; E-mail: inai.yoshihito@nitech.ac.jp
Helical structure originally promotes one-handed sense through
chiral stimuli that are covalently or noncovalently incorporated
there, even if the chiral/achiral ratio or enantiomeric bias is
considerably small.1 This chiral amplification readily creates
homochiral nature in protein helices, which definitely choose a right-
handed sense synchronized with the asymmetric conformation of
most L-residues.2 Despite the strong preference for right-handedness,
a heterochiral nature is found in protein helices. The helix
Figure 1. Induction of a heterochiral helix through the Schellman motif.3
C-terminus (usually Gly) often favors a left-handed helical con-
formation, defined as the “Schellman motif”.3 This motif thus is
regarded as a local heterochiral structure.
We report the formation of a heterochiral helix by increasing
the chain length of single chirality, without using any L/D-
sequences.4,5 Peptides composed of L-sequences at the N-terminal
side and the following achiral sequence are adopted here. A
propensity for a left-handed helix sense in the achiral segment
becomes more pronounced against increasing content of the
L-residue favoring a right-handed sense. When the L-sequence
reaches a sufficient length, the helical sense tends to be switched
around the boundary of the chiral/achiral sequence. We propose a
nucleation model of a heterochiral helix through the covalent chiral
domino effect6 derived from the Schellman motif3 (Figure 1).7
Figure 2. CD (upper) and absorption spectra of (A) peptides N1-NP in
1,2-dichloroethane, and (B) peptide NP in several solvents; ∆ꢀ and ꢀ are
expressed in terms of ∆ZPhe residue concentration.
We have demonstrated these issues with a series of chiral/achiral
block-type peptides (N18-N5 and NP). The L-Leu sequence with
a sufficient length will form a right-handed helix.9 The achiral part
is based on R-aminoisobutyric acid (Aib) and (Z)-R,â-dehydro-
phenylalanine (∆ZPhe) residues to form the optically inactive
helix.6e-g,10 Absorption band of the latter residue, free from those
of usual solvents or peptide bonds, enables us to identify helix sense
induced in the achiral segment.4b,6d-g
L-residue number. Peptides N3 and N4 also adopted a right-handed
helix. However, the CD intensity around 280 nm decreased with
the chiral length, indicating that the right-handed helicity of the
achiral sequence becomes less prominent in elongation of the L-Leu
length. Intriguingly, peptides N5 and NP having longer L-sequences
produced a split pattern opposite to the case of N2-N4. Obviously,
the left-handed helicity appears in the achiral segment of N5 and
NP. In Figure 2A, an isodichroic point12 among N2-NP seems to
appear at ca. 288 nm, suggesting varying ratios of two common
conformers in the achiral sequence. Increasing the L-sequence length
shifts dynamic equilibrium of the two helical populations toward a
left-handed helicity.
In 2,2,2-trifluoroethanol (Figure 2B), peptide NP yielded a pattern
at the amide region, typically assigned to a right-handed R-helix,13
in which the L-Leu sequence reasonably adopts a right-handed helix.
In contrast, a split pattern for the left-handed helicity was found at
the ∆ZPhe chromophores of the achiral segment. Consequently, the
helical inversion occurs around the chiral/achiral boundary on a
single chain of peptide NP as proposed in Figure 1.
IR and NMR studies on peptides N1-N5 suggested the presence
of 310-helical conformation.11 Amide I absorption of NP implied
an R-helical conformation in the Leu segment.11
CD spectra of these peptides were acquired in several solvents.
They mostly showed a split CD pattern around 280 nm based on
the achiral ∆ZPhe residue (Figure 2 and ref 11). The split profile
has been interpreted as the helix sense of -(∆ZPhe-X)m- in a 310-
helix.6f A split sign with positive signals (at longer wavelength) is
assigned to a left-handed helix.6f In addition, the CD amplitude
implies efficiency of chiral induction in the achiral sequence.
Figure 2A displays CD spectra of peptides N1-NP at room
temperature. Peptide N1 favored a left-handed helix in solution as
reported previously.6g,8 In contrast, the N-terminal homochiral
doublets (N2) induced a right-handed helix, suggesting the reason-
able tendency to promote a right-handed helicity by increasing the
Helix sense induction through the covalent domino effect has
been widely proposed in other unique molecules, in which the chiral
sign of a chain-terminal moiety plays a key role.6,14 In contrast,
the present induction of helicity in the achiral segment varies with
the preceding homochiral length, whereas the L-Leu residue is
commonly located at the chiral/achiral boundary of N1-NP. This
9
14736
J. AM. CHEM. SOC. 2006, 128, 14736-14737
10.1021/ja063873n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Supporting Information Available: Theoretical energy calculation,
characterization, spectroscopic data, and discussion. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893-4011. (b) Nakano, T.; Okamoto, Y. Chem.
ReV. 2001, 101, 4013-4038. (c) Yashima, E.; Maeda, K.; Nishimura, T.
Chem.sEur. J. 2004, 10, 42-51. (d) Green, M. M.; Peterson, N. C.; Sato,
T.; Teramoto, A.; Cook, R.; Lifson, S. Science 1995, 268, 1860-1866.
(2) Zimmerman, S. S.; Pottle, M. S.; Ne´methy, G.; Scheraga, H. A.
Macromolecules 1977, 10, 1-9.
(3) For helical reversal at the C-terminus, see: (a) Schellman, C. In Protein
Folding; Jaenicke, R., Ed.; North-Holland Biomedical Press, Elsevier:
Amsterdam, 1980; pp 53-61. (b) Aurora, R.; Srinivasan, R.; Rose, G. D.
Science 1994, 264, 1126-1130. (c) Sagermann, M.; Mårtensson, L.-G.;
Baase, W. A.; Matthews, B. W. Protein Sci. 2002, 11, 516-521. (d) Bang,
D.; Gribenko, A. V.; Tereshko, V.; Kossiakoff, A. A.; Kent, S. B.;
Makhatadze, G. I. Nat. Chem. Biol. 2006, 2, 139-143.
(4) An L/D-block-type peptide was demonstrated to adopt a unique heterochiral
helix: (a) Banerjee, A.; Raghothama, S. R.; Karle, I. L.; Balaram, P.
Biopolymers 1996, 39, 279-285. For homochiral/heterochiral helices along
a single chain, see also: (b) Rudresh; Ramakumar, S.; Ramagopal, U.
A.; Inai, Y.; Goel, S.; Sahal, D.; Chauhan, V. S. Structure 2004, 12, 389-
396. (c) Aravinda, S.; Shamala, N.; Bandyopadhyay, A.; Balaram, P. J.
Am. Chem. Soc. 2003, 125, 15065-15075. Polypeptide linking two types
of L-sequences undergoes unique thermal-driven helix inversion: (d)
Ushiyama, A.; Furuya, H.; Abe, A.; Yamazaki, T. Polym. J. 2002, 34,
450-454.
(5) For elegant simulation of heterochiral and homochiral helices, see: (a)
Nanda, V.; Degrado, W. F. J. Am. Chem. Soc. 2004, 126, 14459-14467.
(b) Nanda, V.; Degrado, W. F. J. Am. Chem. Soc. 2006, 128, 809-816.
(6) For the domino-type induction of helicity, see: (a) Okamoto, Y.; Matsuda,
M.; Nakano, T.; Yashima, E. Polym. J. 1993, 25, 391-396. (b) Dolain,
C.; Jiang, H.; Le´ger, J.-M.; Guionneau, P.; Huc, I. J. Am. Chem. Soc.
2005, 127, 12943-12951. (c) Mazaleyrat, J.-P.; Wright, K.; Gaucher, A.;
Toulemonde, N.; Wakselman, M.; Oancea, S.; Peggion, C.; Formaggio,
F.; Setnicˇka, V.: Keiderling, T. A.; Toniolo, C. J. Am. Chem. Soc. 2004,
126, 12874-12879. (d) Pieroni, O.; Fissi, A.; Pratesi, C.; Temussi, P. A.;
Ciardelli, F. J. Am. Chem. Soc. 1991, 113, 6338-6340. (e) Inai, Y.;
Tagawa, K.; Takasu, A.; Hirabayashi, T.; Oshikawa, T.; Yamashita, M.
J. Am. Chem. Soc. 2000, 122, 11731-11732. (f) Inai, Y.; Ousaka, N.;
Okabe, T. J. Am. Chem. Soc. 2003, 125, 8151-8162. (g) Inai, Y.; Ashitaka,
S.; Hirabayashi, T. Polym. J. 1999, 31, 246-253.
Figure 3. Heterochiral helix (type I) and homochiral helix (type II)
simulated in acetyl-L-Ala20-(Aib-∆ZPhe)4-Aib-OMe.18 The chiral segment
(light-red carbon) adopts an essentially right-handed R-helix. In type I, the
achiral segment (blue carbon) takes a left-handed 310-helix, in which the
red arrow indicates 6 f 1 and 5 f 2 hydrogen bonds for the Schellman
motif.3,4c,5a,7a
chiral length effect originates from not only chirality of the boundary
L-Leu but also conformational asymmetry of the preceding L-
sequence. Thus, left-handed helicity in NP is induced through the
C-terminal inversion of the right-handed R-helix.
CD data in other solvents are summarized in ref 11. Dichlo-
romethane and chloroform showed a similar tendency: elongation
of the L-sequence weakens the preference for a right-handed helicity,
commonly inducing a left-handed helicity in NP. Acetonitrile or
alcohols led to induction of left-handed helicity in N1-N5. NP
also underwent induction of the left-handed helix in methanol,
ethanol, and 2-methyl-1-propanol, while the split pattern was
somewhat distorted in tetrahydrofuran. In the three alcohols, left-
handed helical tendency in N4, N5, and NP seems to be promoted
with the L-sequence length. In most solvents (Figure 2B), the achiral
sequence of NP prefers a left-handed helicity. This solvent-
insensitive formation of a heterochiral helix might be consistent
with the view that conformational inversion at the C-terminal Gly
of an R-helix is based on stereochemical origin rather than solvent
effect.3d
Such a heterochiral helical structure was simulated by semiem-
pirical MO (AM1)11,15 computation. A stable structure found (type
I, Figure 3) involves 6 f 1 and 5 f 2 hydrogen bonds for the
Schellman motif at the boundary, favoring a bending form.3,4c,5a,7a
In contrast, the homochiral helix (type II, Figure 3) preferred a
more straight form.16 Here the type I was predicted to be slightly
more preferential in solution.17 Thus the heterochiral helix might
be stabilized in solution through local inversion in helix sense and
molecular shape advantageous to solvent effects.17
Consequently, we have demonstrated that a heterochiral helix
can be induced through the chiral switch generated by the
L-sequence length. In other words, the local inversion derived from
the Schellman motif is proven to nucleate the helix sense in the
following achiral segment to function as the domino effect, when
the segment is composed of strong helical inducers. These findings
not only provide novel insights into peptide design of a heterochiral
helix but also support an elementary model for homochiral-
heterochiral origins in the evolution of hierarchical structures from
primitive chiral/achiral sequences.5
(7) A helical chain designed delicately with chiral/achiral residues undergoes
chain reversal through the site-specific Schellman motif to exhibit unique
structures: (a) Datta, S.; Uma, M. V.; Shamala, N.; Balaram, P.
Biopolymers 1999, 50, 13-22. (b) Rajashankar, K. R.; Ramakumar, S.;
Mal, T. K.; Jain, R. M.; Chauhan, V. S. Angew. Chem., Int. Ed. Engl.
1996, 35, 765-768. (c) Karle, I. L. Biopolymers 2001, 60, 351-365. See
also ref 4c. In contrast, we have employed a series of the chiral/achiral
block sequences to highlight chain length effect of the N-terminal
L-sequence on induction of a heterochiral helix to demonstrate Figure 1.
For artificial chiral-achiral block polymer, see: (d) Takei, F.; Yanai, K.;
Onitsuka, K.; Takahashi, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1554-
1556.
(8) While solvent effect on helical sense of peptide N1 was partly reported,6g
the present data have been updated for peptide N1 resynthesized. See
also: Inai, Y. Recent Research DeVelopments in Macromolecules;
Research Signpost: India, 2002; Chapter 2.
(9) For helix propensity of amino acid, see: (a) Richardson, J. M.; Lopez,
M. M.; Makhatadze, G. I. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 1413-
1418. Whereas Leu oligomers form a sheet form in the solid state, L-Leu/
Aib block peptides having a proper ratio of the two residues and a
sufficient length promote a helical conformation in solution.9b (b) Isokawa,
S.; Mimura, Y.; Narita, M. Macromolecules 1989, 22, 1280-1284.
(10) Inai, Y.; Oshikawa, T.; Yamashita, M.; Tagawa, K.; Hirabayashi, T.
Biopolymers 2003, 70, 310-322.
(11) See the Supporting Information.
(12) Holtzer, M. E.; Holtzer, A. Biopolymers 1992, 32, 1675-1677.
(13) Sreerama, N.; Woody, R. W. Methods Enzymol. 2004, 383, 318-351.
(14) Stereochemistry of the internal moiety in an artificial backbone was
elegantly demonstrated to promote helix inversion: Dolain, C.; Le´ger,
J.-M.; Delsuc, N.; Gornitzka, H.; Huc, I. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 16146-16151. For unique “helix reversal”, see also 1d.
(15) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am.
Chem. Soc. 1985, 107, 3902-3909. For the detailed procedure and results,
see also ref 11.
(16) The helical axis of type II slightly bends due to a mixed 310/R-helical
hydrogen bonding pattern.11
(17) For more information of a preference for heterochiral helix, see ref 11.
(18) The molecular graphics were drawn with: Thompson, M. A. ArgusLab
4.0.1; Planaria Software LLC: Seattle, WA, 2004 (http://www.arguslab.com).
Acknowledgment. This work was partially supported by the
project (No. 16550142) of the Ministry of Education, Culture,
Sports, Science, and Technology of Japan.
JA063873N
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14737