Chemistry Reference
In-Depth Information
understanding of the diseases caused by protein misfolding and development of
therapeutic drugs. In addition, new design principles have resulted in linking the
primary and secondary structural features and the resultant nanostructures in the fab-
rication of engineered protein-based nanomaterials. Of particular importance is the
work done by Mihara and group (Takahashi et al. 1998, 1999; Takahashi, Ueno
et al. 2000; Takahashi, Yamashita et al. 2000) who developed a series of coiled
coil peptides modified with hydrophobic domains at the N-terminus that self-
assembled into amyloid-like fibers, accompanied by a secondary structural transition
from a-helix to b-sheet.
The secondary structural change is thought to be induced by the partially folded
helix that exposes the hydrophobic regions of peptides in water, thus leading to the
aggregated nanofibers through hydrophobic interaction. Systematic follow-up
mutation studies (Matsumura et al. 2004) have demonstrated the ability to control
the self-assembly of nanofibers by complementary charge interaction and have resulted
in fibers with uniformmorphology. Other groups have also shown an analogous helix-
sheet transition using different peptide models. Woolfson's group (Ciani et al. 2002)
designed a peptide showing “structural duality,” namely, the peptide is compatible
with both a-helix and b-sheet formations. High b-sheet character amino acids (Thr)
were incorporated to enhance the peptide's ability to formb-sheets, whereas the amphi-
philic pattern of the hydrophobic and hydrophilic amino acids allowed the peptide to
self-assemble into an a-helical coiled coil. The peptide containing Thr readily under-
went a thermal-induced formation of b-sheets and nanofibers. Amore detailedmolecu-
lar model for peptides in the fibrillar state was established by Kammerer and coworkers
(2004) with a de novo designed trimeric coiled coil. A 17-residue peptide, referred to as
ccb, forms a native a-helical structure comprising three stranded helices as determined
from X-ray crystal structural analysis. An increase of temperature or ionic strength
promoted the transition to b-sheets, which further self-assembled into nanofibrils,
showing a laminated, off-register antiparallel cross-b structure. Ala at position 7
hydrogen bonds to Leu at position 14 as evidenced by rotational echo double resonance
measurements (Fig. 14.5). Recently, a two-stranded ccb coiled coil dimer was proposed
to have the same effect on the structural transition with a temperature change from 48 to
70 8C (Kammerer and Steinmetz 2006).
While studying of stability of short coiled coil peptides, our group identified the
significance of hydrophobic clusters in promoting the helix-sheet transition and
amyloid formation. The amino acids involved in the formation of a tentative hydro-
phobic cluster (Fig. 14.6 at a, d, and f positions) have been extensively studied for
their ability to form either a stable helix or induce the helix to sheet transition in
both two-heptad and three-heptad model systems (Dong and Hartgerink 2006,
2007). Five different amino acids (Gln, Ser, Tyr, Leu, and Phe) were incorporated
in the f positions. These amino acids were chosen to allow the peptides having differ-
ent secondary structural propensity and alternating hydrophilic-hydrophobic pattern.
Experiments demonstrated that the secondary structural transition is independent
of the amino acid secondary structural propensity, but it only relies on the peptides'
primary sequence with alternate hydrophobic-hydrophilic residues localized in the
central region.
