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Multi-stranded b-Sheets

The design of multi-stranded b-sheets in both polar and apolar structures is conceptually simple, once the principles of b-hairpin design are established. In considering the design of a multi-stranded b-sheet, it is useful to examine the consequences of introducing strong prime turn forming segments at centrally located positions in designed polypeptide chains, as noted in Section 5.3. Incorporation of strong prime turns forming segments like DPro-Xxx [32-33] and Aib-DXxx [38] promotes hairpin formation. The insertion of such nucleating units at multi

Fig. 5.15 Superposition of 10 NMR derived structures for designed b-sheets: (a) three stranded b-sheet in a 14-residue peptide [49a]; (b) Four stranded b-sheet in a 26-residue peptide [49b], calculated using NOE derived restraints.

Fig. 5.15 Superposition of 10 NMR derived structures for designed b-sheets: (a) three stranded b-sheet in a 14-residue peptide [49a]; (b) Four stranded b-sheet in a 26-residue peptide [49b], calculated using NOE derived restraints.

ple positions in a polypeptide chain may be an effective strategy for the creation of multi-stranded b-sheets [49-51]. This expectation is clearly borne out by several experimental studies on three-, four- and five-stranded b-sheets. Figure 5.15 illustrates examples of multi-stranded b-sheet structures characterized in organic solvents by NMR. Thus far, no crystallographic analysis of a multi-stranded b-sheet prepared by the de novo design approach has been reported. The construction of multi-stranded b-sheet structures stable in organic solvents has proved easier than anticipated because of the driving role of the cross-strand hydrogen bonds in stabilizing b-sheet structures. In b-sheets, the influence of cross-strand side chain-side chain interactions is less dominant, permitting a wide range of strand segments to be chosen. Multi-stranded sheets may be viewed as examples of tertiary structure formation. Mimics of b-sheet motifs in protein structures have been designed, based on naturally occurring toxin models that are stabilized by disulfide bonds [52]. While aggregation is a problem that is frequently encountered in the design of multi-stranded b-sheet structures [53], the positioning of strongly basic residues Arg/Lys at the N and C termini is an effective strategy to limit peptide self association [7a].

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