New cyclic peptide assemblies with hydrophobic cavities: The structural and thermodynamic basis of a new class of peptide nanotubes

Article abstract of DOI:10.1021/ja0296273

A new class of self-assembling peptides based on cyclic peptides made of alternating 3-aminocyclohexanecarboxylic acid (γ-Acc) and α-amino acids is described. The studied cylindrical assemblies are models for a new class of self-assembling peptide nanotub

Full text of DOI:10.1021/ja0296273

Published on Web 02/19/2003
New Cyclic Peptide Assemblies with Hydrophobic Cavities: The Structural
and Thermodynamic Basis of a New Class of Peptide Nanotubes
Manuel Amor´ın, Luis Castedo, and Juan R. Granja*
Departamento de Qu´ımica Orga´nica e Unidade Asociada o´ C.S.I.C., Facultade de Qu´ımica,
UniVersidade de Santiago, 15782 Santiago de Compostela, Spain
Received December 7, 2002 ; E-mail: qojuangg@usc.es
In recent years, considerable effort has been devoted to the
synthesis of organic and inorganic nanotubes.1 Self-assembling
peptide nanotubes (SPN) made from cyclic D,L-R-peptides2 or from
cyclic â-peptides3 have structural and functional properties that may
be suitable for various applications in biology and materials
science.1b,4-6 Here we describe a new member of self-assembling
peptides with novel structural and internal cavity, validating the
possibility of expanding the SPN class to other hybrid systems.
The present structures are based on a hybrid of R-γ-cyclic peptides7
subunits and have been characterized by NMR, FT-IR, and X-ray
crystallography.
Cyclic peptides in which (1R,3S)-3-aminocyclohexanecarboxylic
acid (γ-Acc-OH) alternates with a D-R-amino acid, such as 1a, can
adopt a conformation in which the peptide backbone is essentially
flat and the CdO and NsH groups lie roughly perpendicular to
the plane of this cyclic backbone (Figure 1). This flat ring-shaped
conformation may facilitate antiparallel â-sheetlike hydrogen bond-
ing between oppositely oriented rings and the formation of
hydrogen-bonded nanotubes composed of rings of alternating
orientation, in which one face of each ring is hydrogen-bonded via
γ-Acc CdO and NsH groups to the similar face of the neighbor
(Figure 1, frame A), while the other face is hydrogen-bonded via
CdO and NsH groups of the R-amino acid to the similar face of
the other neighbor (Figure 1, frame B). In such structures, the
â-methylene moiety of each cyclohexane is projected into the lumen
of the cylinder, creating a partial hydrophobic cavity.
ically, cyclopeptide 1b, in which the R-amino acids are N-
methylated, was used to prepare dimer 2b, which features A-type
hydrogen-bonding (Figure 1), and cyclopeptide 1c, in which all
γ-Acc are N-methylated (MeN-γ-Acc), was used to prepare staked
dimeric ensemble 2c, which features Figure 1B-type hydrogen
bonding.
The cyclo peptides cyclo-[(1R,3S)-γ-Acc-D-MeNAla]3 (1b, R )
Me) and cyclo-[D-Phe-(1R,3S)-MeN-γ-Acc]3 (1c, R ) Bn) were
synthesized by standard procedures and characterized by NMR and
1
MS. The H NMR spectra of the peptide 1b, in both polar and
nonpolar solvents (CCl4, CDCl3, MeOH, or DMSO), are well
defined, highly symmetrical, and show a JNH,γH coupling constant
of 7.5-8.2 Hz, indications that the peptide exists in an all-trans
conformation with a flat-ring-shaped backbone. In nonpolar sol-
vents, the formation of dimers is reflected by the downfield shift
upon increasing the concentration of the N-H resonance of γ-Acc
from δ 6.6 to 7.8 ppm;9 the corresponding association constant,
determined at 298 K by dilution experiments, is 230 M-1 in CDCl3
and 2.5 × 104 M-1 in 2:3 CDCl3/CCl4. Van’t Hoff plots for the
range 273-313 K afford values of -34.1 KJ mol-1 for ∆H°298
and -69.8 J/K‚mol for ∆S°298 that, like the fall in Ka with increasing
solvent polarity, are consistent with dimerization being essentially
an enthalpy-driven10 hydrogen-bonding process.8a,c The â-sheet
nature of the hydrogen bonding is also supported by the chemical
shift of MeN-Ala CR undergoing a concentration-dependent down-
field shift of > 0.1 ppm11 and by FT-IR spectra recorded in CHCl3,
To establish and evaluate the feasibility and the thermodynamic
properties of such nanotubes, we prepared dimers featuring each
of the two hydrogen-bonding patterns described above, using cyclic
peptides in which hydrogen bond donation from one face of the
ring structure was blocked by N-methylation (Figure 2).8 Specif-
which show amide I and amide IIii bands at 1626 and 1538 cm-1
,
respectively (positions that are typical of â-sheets and similar to
those found for nanotubes and dimers composed of cyclic D,L-
peptides). Hydrogen bonding by N-H is further supported by amide
A bands near 3325 cm-1, while a band that appears at 3400 cm-1
Figure 1. Design for self-assembling peptide nanotubes composed of cyclo-[(1R,3S)-γ-Acc-D-Aa]3 units (for clarity, amino acid side chains have been
omitted in the representation of the nanotube and dimers). The two different H-bonding patterns (A and B) are shown in different colors. Dimers used to
study the basic parameters of the proposed self-assembling nanotube are shown at the right.
9
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J. AM. CHEM. SOC. 2003, 125, 2844-2845
10.1021/ja0296273 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
to nanotubes with greater selectivity as ion channels, catalysts,
receptors, or molecule containers. Work is in progress to this end.
Acknowledgment. This work was supported by Ministerios de
Educacio´n y Ciencia and Ciencia y Tecnolog´ıa and the Xunta de
Galicia under Projects PB97-0524, SAF2001-3120, and
PGIDT00PXI20912PR, respectively, and through a research grant
to M.A.
Supporting Information Available: Detailed descriptions of the
synthesis and characterization of key compounds and crystal data,
atomic coordinates, bond lengths and angles, and anisotropic displace-
ment coefficients of 1c. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 2. Crystal structures of dimeric assemblies 2c with five molecules
of chloroform, one of which occupies the central cavity of the dimer: (left)
top view; (right) side view.
in more dilute (0.5 M) solutions may correspond to the N-H band
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1
both the dimer (at 7.84 ppm) and the monomer (at 6.54 ppm), H NMR
spectrum is available in the Supporting Information.
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8c. The 1H NMR spectrum of 1b recorded in CH2Cl2 at 189 K, showing
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ppm, respectively), is available in the Supporting Information, as are room-
temperature spectra showing the CRH signal shifting with increasing
concentration.
(12) Engels, M.; Bashford, D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117,
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