Published on Web 02/27/2002
A Noncovalent Approach to Antiparallel â-Sheet Formation
Huaqiang Zeng,† Xiaowu Yang,† Robert A. Flowers, II,§ and Bing Gong*,†
Contribution from the Department of Chemistry, Natural Sciences Complex, State UniVersity of
New York, Buffalo, New York 14260, and Department of Chemistry and Biochemistry,
Texas Tech UniVersity, Box 41061, Lubbock, Texas 79409-1061.
Received March 16, 2001
Abstract: Four tripeptide chains, when attached to the same end of a hydrogen-bonded duplex (1‚2) with
the unsymmetrical, complementary sequences of ADAA/DADD, have been brought into proximity, leading
to the formation of four hybrid duplexes, 1a‚2a, 1a‚2b, 1b‚2a, and 1b‚2b, each of which contains a two-
stranded â-sheet segment. The extended conformations of the peptide chains were confirmed by 1D and
2D NMR. The peptide strands stay registered through hydrogen bonding and the â-sheets are stabilized
by side chain interactions. Two-dimensional NMR data also indicate that the duplex template prevents
further aggregation in the peptide segment. When the peptide chains are attached to the two different
termini of the duplex template, NMR studies show the presence of a mixture with no clearly defined
conformations. In the absence of the duplex template, the tripeptides are found to associate randomly.
Finally, isothermal titration calorimetry studies revealed that the hybrid duplex 1a‚2a was more stable than
either the duplex template or the peptides alone.
Introduction
stability of the resulting â-hairpins and related model structures
is found to depend on hydrogen bonding, side chain interactions,
Understanding â-sheet formation is critical to many problems
and applications involving protein folding and design. Discern-
ing the factors affecting â-sheet structure and stability may
eventually lead to novel peptide antibiotics,1-3 and to treatments
for diseases in which â-sheet formation plays a key role.4,5
Although as common as the R-helical structure in proteins, the
â-sheet secondary structure is not well understood due to the
lack of well-defined â-sheets amenable to detailed biophysical
evaluation. Current efforts in developing model systems of
â-sheets are focused on the design of short peptides that fold
in solutions.6-17 Artificial systems consisting of â-strands linked
by unnatural templates have also been described.18-20 The
and the types of â-turns and turn mimetics. We report here the
nucleation of antiparallel â-sheet-like structures based on a
noncovalent, self-assembling approach.
We recently described hydrogen-bonded duplexes based on
linear oligoamide strands bearing arrays of hydrogen-bonded
donors (D) and acceptors (A).21-24 These molecular duplexes
are formed by pairing two single strands of complementary
hydrogen-bonding sequences. The formation of these duplexes
is highly sequence-specific: a single strand only pairs with
another strand of its complementary sequence. Due to the
absence of secondary electrostatic interactions25-27 in this
system, the stability of a duplex is sequence-independent and
is proportional to the number of H-bonds found in that duplex.
Both the H-bonding sequences and the number of H-bonding
sites in a duplex are easily adjustable. Since the single strands
of the H-bonded duplexes adopt an extended conformation
similar to that of â-strands, these single strands can be regarded
as â-strand mimics and the corresponding duplexes as two-
stranded â-sheet mimics. Indeed, the interstrand distance of a
† State University of New York.
§ Texas Tech University.
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J. AM. CHEM. SOC. VOL. 124, NO. 12, 2002 2903