This paper discusses the recent developments of protein engineering using both covalent and noncovalent bonds to constrain peptides, forcing them into designed protein secondary structures. These constrained peptides subsequently can be used as peptidomimetics for biological functions such as regulations of protein-protein interactions. 1. Stabilized and Destabilized -Helices α-Helices have been found to be the secondary structure about 40% of all residues in natural proteins adopt [1], and they are widely used as fundamental recognition elements in many naturally occurring protein complexes, such as Bcl-2/Bak, MDM2/p53, calmodulin/smooth-muscle-myosin-light-chain kinase, Vav/DH domain, and CREB/CBP [2–5]. A typical α-helix completes one rotation with 3.6 amino acid residues, in which each has backbone dihedral angles of and [6]. This results in the helix having a rise of 1.5？？/residue or 5.4？？/turn [7]. Therefore, the side chain of a certain residue at the position projects from the same face with the side chains at the and the positions in the sequence (Figure 1). The backbone of the α-helix is primarily stabilized by hydrogen bonds between the carbonyl of residues and the carboamide of residues , which all point in the same direction [6]. Because the hydrogen bonding sites on the first and last turns of an α-helix are unfulfilled, a macrodipole is produced [8, 9]. The positive end of the dipole is centered at the N-terminus and the negative at the C-terminus. The total dipole is augmented if the peptide existed in conditions where both the termini are ionized. Figure 1: The structure of an α-helix. (a) The helical wheel diagram. (b) Surface displacement of residues on an α-helix surface. It can be imagined that isolated helical peptides would be ideal inhibitors of macromolecular interactions [10]. However, because many peptides, especially those with less than ten residues, rarely contain sizable degrees of helicity in isolation, much work has been done toward the goal of helix induction and stabilization [11]. The goal of this paper is to highlight the chemical strategies employed to stabilize protein secondary structures and the applications of the constrained peptides in regulating protein-protein interactions. 1.1. Covalent Stabilization The formation of covalent linkages between adjacent residues in peptides has been shown to impart stabilization to the helical form of the peptide. Disulfide bonds, lactam linkages, hydrazones, and carbon-carbon bonds have all been used to link to or residues in a peptide and promote helicity (Figure 2). The
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