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Helix-Helix Motifs

The ability to construct relatively rigid helical peptide modules can be used to advantage in the creation of larger designed structures, in which distinct helical segments are connected by a non-helical linking loop. The orientation of two helical modules will then be determined by the conformational properties of the linking segment. Several attempts have been reported to design antiparallel helix-helix motifs using an Aib-rich helical module. In these cases, Gly, Pro and d-amino acids containing loop segments, generally 2-3 residues in length have been employed. The crystal structures of some representative examples reveal an extended arrangement of the two linked modules. Optimization of side-chain interactions has provided a well characterized example of a helix-loop-helix motif in the pep-

Helical Coordinates

Fig. 5.14 (a) Helix-turn-helix structure of the peptide Ac-Gly-APhe-D-Ala-APhe-APhe-D-Ala-APhe-APhe-L-Ala-(Gly)4-APhe-L-Ala-L-Leu-APhe-L-Ala-L-Leu-APhe-L-Ala-NHMe [42]; (b) a view of the side chain-side chain interactions showing short distances (A) [42]. Figures generated using the coordinate set CCDC-153089 [www.ccdc.cam.ac.uk/].

Fig. 5.14 (a) Helix-turn-helix structure of the peptide Ac-Gly-APhe-D-Ala-APhe-APhe-D-Ala-APhe-APhe-L-Ala-(Gly)4-APhe-L-Ala-L-Leu-APhe-L-Ala-L-Leu-APhe-L-Ala-NHMe [42]; (b) a view of the side chain-side chain interactions showing short distances (A) [42]. Figures generated using the coordinate set CCDC-153089 [www.ccdc.cam.ac.uk/].

tide Ac-Gly-APhe-d-Ala-APhe-APhe-d-Ala-APhe-APhe-l-Ala-(Gly)4-APhe-l-Ala-l-Leu-APhe-l-Ala-l-Leu-APhe-l-Ala-NHMe shown in Fig. 5.14 [42]. In this case, favorable aromatic-aromatic interactions facilitate the formation of a compact structure. In the case of water-soluble peptides, hydrophobic interactions may be used to advantage to drive the de novo designed structures into condensed conformations, with solvent forces providing a major impetus for compaction. In such cases, fragment design utilizes the principles of patterning polar and apolar residues in such a manner that there is a clear segregation of residues of one type on distinct faces of the molecule, once secondary structures are formed [5]. The generation of apolar faces permits secondary structure association in apolar tertiary interactions. Table 5.3 lists some representative examples of helix bundles generated by de novo design [43-46].

Another approach which has been successfully employed is the use of metal ions as templates with ligating group positioned on distinct secondary structure elements forced to proximity by metal-ligand interactions [47]. Mutter and coworkers have advanced the use of rigid scaffolds to position helical segments in proximity, resulting in systems that have been termed template-assembled synthetic proteins (TASP) [48].

The design of helix-helix motifs in apolar solvents requires substantial control over the conformational properties of the linking segment and an appreciation of the geometrical features of the weakly polar interactions that may be used to control helix-helix orientation. In this approach an understanding of the role of en-tropically stabilizing side chain-side chain interactions is especially necessary.

Table 5.3 Representative examples of designed water-soluble supersecondary structures.

Molecule Technique Reference a-helix (a-1 at low pH; 1AL1)a (13 residues) X-ray crystallography 43a a-helix (a-1 near neutral pH; 1BYZ)° (13 residues) X-ray crystallography 43b

Four-helix bundle (Peptidergent; single polypeptide X-ray crystallography 44a chain; 4HB1) (108 amino acids)

Triple-stranded coiled-coil (Coil-Ser; 1COS) (31 X-ray crystallography 43e residues/chain)

Triple-stranded coiled-coil (Coil-Vald; 1COI) (31 X-ray crystallography 43c residues/chain)

Trimeric coiled-coil (1BB1) (36 residues/chain) X-ray crystallography 44b

Trimeric coiled-coil (1GCM) (34 residues/chain) X-ray crystallography 44c

Tetrameric coiled-coil (1GCL) (34 residues/chain) X-ray crystallography 44d

Right-handed, tetrameric coiled-coil (1RH4) (35 X-ray crystallography 44e residues/chain)

Four-helix bundle with a diiron-binding center X-ray crystallography 43d (association of two helix-loop-helix motifs) (Due Ferro 1; 1EC5) (50 residues/chain)

Helical hairpin (RtR; 1ABZ) (40 residues) NMR 44e

Helical hairpin (R-2D; 1QP6) (35 residues) NMR 45a bba Motif (1FSD) (28 residues) NMR 45b bba Motif (1PSV) (28 residues) NMR 45c

Three-helix bundle (single polypeptide chain; 2A3D) NMR 46a-b (73 residues)

a These are single helices, but the discussion of crystal state aggregation may be relevant to supersecondary structure design.

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