good crystals. Determination of the molecular basis of
recognition and self-assembly process that govern amyloid
fibril formation is therefore a very challenging task. So, short
model peptides, which provide valuable information about
the factors responsible for amyloid formation are of crucial
importance.
behavior, and these fibrils are toxic towards the Neuro 2A
cell line. We have also synthesized two mutant tripeptides
in which the centrally positioned amino acid residue has been
substituted by other proteinous aromatic amino acid phenay-
lalanine (Phe) or tryptophan (Trp) to examine whether these
tripeptides can form amyloid-like fibrils and exhibit neuro-
toxicity. Figure 1 shows chemical structures of reported
peptides 1, 2, and 3.
Westermark and co-workers have carried out pioneering
work on the use of model peptides for the study of amyloid
fibril formation.6 Serranno et al. have shown the residue-
specific tendency for amyloid fibrilation in a series of model
hexapeptides.7 Gazit et al. have illustrated the self-aggrega-
tion of short peptide fragments into amyloid fibrils and
established the role of an aromatic residue (phenylalanine)
in amyloidosis.8 Serpell et al. have described the self-
association of an amyloid-forming 12-residue peptide in the
solid state, and the structure illustrates the molecular ar-
rangement of the amyloid fibril forming peptide in crystals
showing a tentative model for side-chain packing within the
amyloid fiber.9 Mihara et al. have recently reported that a
series of designed short peptides with various hydrophobici-
ties based on the sequence of Aꢀ(14-23) can form amyloid-
like fibrils effectively by using mature Aꢀ(1-42) fibrils as
nuclei.10 Recent studies have also demonstrated that the
fundamental unit of amyloid-like fibrils is a steric zipper
formed by two tightly interdigited ꢀ-sheets.11
Figure 1. Chemical structures of peptides 1, 2, and 3.
Our group has been engaged in studying the self-assembly
of short model peptides which form supramolecular ꢀ-sheets
and amyloid-like fibrils upon self-association.12 It has been
found that C-terminal portion of the full length Aꢀ peptide
has a definitive role in amyloid fibril formation.13 So, there
is a need to test whether any fragment from N-terminal
hydrophilic region can from amyloid-like fibrils or not. Gazit
and his co-workers have made a seminal contribution in the
self-assembly of very short peptide unit Phe-Phe.14 In this
report, we present the self-assembly of the water soluble
tripeptide having sequence identity with the N-terminal
segment of Aꢀ peptide Aꢀ(9-11), GYE, peptide 1, which
forms intermolecularly hydrogen-bonded supramolecular
ꢀ-sheet structure in crystals and in solution. It also forms
straight, unbranched nanofibrils that exhibit amyloid-like
FT-IR spectroscopic studies were carried out to obtain
structural information in the solid state and in solution. The
FT-IR spectra of peptide 1 in the solid state shows a well-
defined CdO stretching band (amide I) at 1637.5 cm-1 and
NH-stretching band at 3280 cm-1, typical of intermolecularly
hydrogen-bonded ꢀ-sheet structure in the solid state (Figure
S8).15a Moreover, peptide 1 shows a medium-intensity band
at 1678 cm-1 indicating the formation of an antiparallel
ꢀ-sheet structure in the solid state. N-H bending frequencies
of this peptide appear at 1515 cm-1 suggesting also the
formation of a ꢀ-sheet structure.15b On the other hand,
peptides 2 and 3 show a sharp CdO stretching band at
1666.4 and 1670 cm-1, respectively, which clearly indicates
that peptides 2 and 3 do not form the ꢀ-sheet structure in
the solid state.16 FTIR spectra of solutions contaning peptides
1 and 3, aged over 7 days, shows a sharp CdO stretching
(amide I) band at 1617 and 1620 cm-1, which indicates the
H-bonded supramolecular ꢀ-sheet conformation in solution
(Figure S9). On the other hand, a similarly aged solution of
peptide 2 shows a characteristic CdO stretching band at 1653
cm-1, indicating its random coil conformation.17
(6) (a) Westermark, P.; Engstro¨m, U.; Johnson, K. H.; Westermark,
G. T.; Betsholtz, C. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 5036–5040. (b)
Ha¨ggqvist., B.; Na¨slund, J.; Sletten, K.; Westermark, G. T.; Mucchiano,
G.; Tjernberg, L. O.; Nordstedt, C.; Engstro¨m, U.; Westermark., P. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 8669–8674.
(7) Paz, Manuela.; Serranno, L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
87–92.
(8) Azriel, R.; Gazit, E. J. Biol. Chem. 2001, 276, 34156–34161.
(9) Makin, O. S.; Atkins, E.; Sikorski, P.; Johansson, J.; Serpell, L. C.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 315–320.
(10) Sato, J.; Takahashi, T.; Oshima, H.; Matsumura, S.; Mihara, H.
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The conformational analysis of peptide 1 in solid state
from FT-IR spectroscopy was further supported by a single-
crystal X-ray diffraction study.18 Colorless, needle-shaped
(11) Sawaya, M. R.; Sambashivan, S.; Nelson, R.; Ivanova, M. I.;
Sievers, S. A.; Apostol, M. I., Thompson, M. J.; Balbirnie, M.; Wiltzius,
J. J. W.; McFarlane, H. T.; Madsen, A. Ø.; Riekel, C, Eisenberg, D., Nature
2007, 447, 453-457.
(12) (a) Maji, S. K.; Drew, M. G. B.; Banerjee, A. Chem. Commun.
2001, 1446–1447. (b) Banerjee, A.; Maji, S. K.; Drew, M. G. B.; Halder,
D.; Das, A. K.; Banerjee, A. Tetrahedron 2004, 60, 5935-5944. (c) Ray,
S.; Das, A. K.; Drew, M. G. B.; Banerjee, A. Chem. Commun. 2006, 4230–
4232.
(15) (a) Mazor, Y.; Gilead, S.; Benhar, I.; Gazit, E. J. Mol. Biol. 2002,
322, 1013–1024. (b) Moretto, V.; Crisma, M.; Bonora, G. M.; Toniolo, C.;
Balaram, H.; Balaram, P. Macromolecules 1989, 22, 2939–2944.
(16) Kenndy, D. F.; Crisma, M.; Toniolo, C.; Chapman, D. Biochemistry
1991, 30, 6541–6548.
(13) Jarrett, T. Joseph.; Berger, P. Elizabath.; Lanbury, T. Peter.
Biochemistry 1993, 32, 4693–4697.
(17) Hu, X.; Kaplan, D.; Cebe, P. Macromolecules 2006, 39, 6161–
6170.
(14) Raches, M.; Gazit, E. Science 2003, 300, 625–627.
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Org. Lett., Vol. 10, No. 13, 2008