Toward Intelligent Materials - Molecular Self-Assembly: Advances and Applications - page 12

interactions, but this is certainly not always the case. For example,
the A

β

(10-35) [60] and A

β

(1-40) [69] peptides assemble as parallel

in-register -sheet assemblies, but a single substitution at the

same residue, A

β

(1-40)D23N, switches the strand orientation [70]
and argues that key constraints can have global impact on these
cooperative assemblies. The much larger prions characteristically
are rich in glutamine and asparagine residues, and the A

β

(16-22)
E22Q peptide was prepared to probe these interactions. Using these
same structural methods, the E22Q peptide was found to assemble
with parallel in-register strands [71], consistent with the self-
complementary cross-strand pairing of Q-Q (Fig. 1.7C) dominating
the folding energetics in this simple peptide model. The importance
of strand registry in prion biology has not been investigated, but
clearly this interaction can contribute to the accessible cross-

β

β

polymorphs.
Significant evidence now also implicates metal binding in
amyloid toxicity [72-74], and these specific structures may well be
therapeutically relevant [74-80]. Metal binding has been extensively
explored in -helical domains and is consequently much better

understood. A recent example in higher order assembly is seen in
the

α

design of a trimeric coiled-coil peptide sequence —
T1ZH [37]. Coiled-coil peptide sequences consist of a seven-residue
repeat, with the positions within the repeat labeled

de novo

abcdefg . Upon

formation of a helix, residues at positions in the coiled-coil

heptad motif are found at the peptide-peptide interface. The T1ZH
3-helix bundle incorporates histidine residues at core d-positions
of alternate heptads in the coiled-coil motif [37]. Assembly into
fibers occurs in the presence of Ag(I) (Fig. 1.1D), but these peptides
remained random coil in the presence of Ni(II), Zn(II), and Cu(II). By
incorporating metal ligands within the internal core of the coiled-
coil assemblies, a cavity that preferentially accommodated trigonal
coordination geometry was created to control selectivity. Thus, the
rational design of selective metal ion binding sites within coiled-coils
has been designed and bottom-up programming of these peptide
interfaces is possible.

a and d

Combining this perspective with insights from the cross-

β

structural models, metal-binding sites were explored as a strategy
to control cross- assemblies. Based on F-F packing models and

molecular dynamic simulations of A

β

β

(16-22), histidines were