Templates for aHelix Stabilization

The above mentioned hypothesis that peptide primary sequences are translated into well defined three-dimensional conformations has stimulated many attempts to derive specific rules for secondary structure formation by short lengths of polypeptides [22]. The a-helix, one of the two most widely occurring secondary structures in proteins, has been the focus of several investigations aiming at analysis of effects of sequence on stability [23]. Helices are classified as repetitive secondary structure because their backbone dihedral angles, f and c, have repeating values near the canonical value of (—60°, —40°). When the dihedral angles of a chain segment assume helical values, the carbonyl group of amino acid residue i is positioned to form a hydrogen bond with an NH function of an amino acid in position i + 4.

According to the Zimm-Bragg theory and related models of the helix-coil transition in polypeptides short helices are very unstable [24]. This assumption is verified by most experimental findings. Helix stabilization thus holds the promise of providing synthetically accessible model systems for studies of protein folding and can also enhance the potencies and/or specificities of bioactive peptides [25]. As a consequence, many efforts have been focused on this direction and several approaches have been reported for stabilizing a-helical peptides, including incorporation of salt bridges [26], metal chelates [27] or amide bonds [28] that bridge the i and i + 4 positions, incorporation of amino acids with high helix propensity [29], and the formation of amphiphilic helix bundles [30] and disulfide bridged peptides [31]. In this context, Kemp and coworkers described the conformationally constrained tripeptide mimic AcHel shown in Figure 1.2.5, that overcomes the nucle-ation penalty for helix formation by providing hydrogen-bond acceptors for the otherwise unsatisfied NH groups in the first helix turn at the N-terminus of a


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