C O M M U N I C A T I O N S
Acknowledgment. This research was supported by the NIH
(GM61238). F.F. is a MEC-Fulbright Postdoctoral Fellow. NMR
spectrometers were purchased in part by grants from NIH and NSF;
diffraction equipment was supported by grants from NSF. We thank
S. H. Choi for growing the crystals of tetrapeptide mimics 1
and 2.
Supporting Information Available: Experimental details, com-
pound characterizations, NMR data and crystallographic data. This
Figure 4. Sequences of 5-8.
in specific tertiary structural contexts, represent substantial sources
of intrinsic secondary structural stability. To probe the significance
of lateral residue pairings in parallel ꢀ-sheet, we prepared 7 and 8,
the sequence isomers of 5 and 6, respectively, in which the
attachment points of the strands to the Gly-CHDA linker have been
swapped (Figure 4). Of the six lateral residue pairings in the hairpin
conformation of 5 or 6, four are altered in the sequence isomers
(two do not change because the residues are identical). In each of
these four asymmetric pairings, the orientation in 5 and 6 is
predicted to be superior to that in 7 and 8, based on the protein
structure database analysis.13 The behavior of 7 and 8 is consistent
with this prediction: 2D NMR data reveal that neither molecule
shows any NOE between protons on sequentially nonadjacent
residues. Thus, neither 7 nor 8 appears to form parallel ꢀ-sheet
secondary structure in aqueous solution. These results show that
the Gly-CHDA linkers are not dominant drivers of parallel ꢀ-sheet
formation; instead, these linkers enable parallel ꢀ-sheet interactions
between attached strands, but interstrand attractions must contribute
to overall conformational stability. Moreover, these results show
that intrinsic ꢀ-sheet propensities of strand residues are not sufficient
to drive folding; instead specific and favorable interactions between
side chains on adjacent strands appear to be necessary for parallel
ꢀ-sheet formation.
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