Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Sunanda Chatterjee Rituparna Sinha Roy P Balaram homologues of a -amino acids Receive free email alerts when new articles cite this article - sign up in the box at the top right-hand corner of the article or click here References Email alerting service REVIEW Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of a-amino acids Sunanda Chatterjee, Rituparna Sinha Roy and P. Balaram* Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India Half a century has passed since the hydrogen-bonded secondary structures of polypeptides and proteins were first recognized. An extraordinary wealth of conformational information is now available on peptides and proteins, which are formed of a-amino acid residues. More recently, the discovery of well-folded structures in oligopeptides containing b-amino acids has focused a great deal of current interest on the conformational properties of peptides constructed from higher homologues (u) of a-amino acids. This review examines the nature of intramolecularly hydrogen-bonded conformations of hybrid peptides formed by amino acid residues, with a varying number of backbone atoms. The b-turn, a ubiquitous structural feature formed by two residue (aa) segments in proteins and peptides, is stabilized by a 10-atom (C10) intramolecular 4/1 hydrogen bond. Hybrid turns may be classified by comparison with their aa counterparts. The available crystallographic information on hydrogen-bonded hybrid turns is surveyed in this review. Several recent examples demonstrate that individual u-amino acid residues and hybrid dipeptide segments may be incorporated into the regular structures of a-peptides. Examples of both peptide helices and hairpins are presented. The present review explores the relationships between folded conformations in hybrid sequences and their counterparts in all a-residue sequences. The use of stereochemically constrained u-residues promises to expand the range of peptide design strategies to include u-amino acids. This approach is exemplified by well-folded structures like the C12 (ag) and C14 (gg) helices formed in short peptides containing multiply substituted g-residues. The achiral g-residue gabapentin is a readily accessible building block in the design of peptides containing g-amino acids. The construction of globular polypeptide structures using diverse hybrid sequences appears to be a realistic possibility. 1. INTRODUCTION A little over 60 years ago, Maurice Huggins reviewed the hydrogen-bonded structures of polypeptide chains, at a time when no detailed structural information was available on oligopeptides and proteins (Huggins 1942, 1943). Attempts to rationalize limited X-ray diffraction data in terms of regular hydrogen-bonded polypeptide structures were summarized by Bragg et al. (1950) in a paper that concluded that there appears a real simplicity of chain structures in myoglobin, which will perhaps be shown by other favourably built proteins. There is hope that the study of such proteins may lead to a reliable determination of structure. This expectation has been amply fulfilled in the last half century with the result that almost every feature of polypeptide chain folding is now firmly established by experimental studies. An interesting feature of the Bragg, Kendrew and Perutz paper is the consideration of intramolecularly hydrogen-bonded structures, which were later shown to be stereochemically and energetically unacceptable. Paulings remarkable insights led to the correct formulation of the hydrogenbonded helical structures of polypeptides (Pauling et al. 1951; Pauling & Corey 1952). One of the last attempts to propose alternative hydrogen-bonded structures was made by Huggins in 1952, when he suggested that a 11-membered hydrogen-bonded ring could be considered as an alternative to Paulings a-helix, which is Review. Expanding the polypeptide backbone S. Chatterjee et al. 150 100 50 50 100 150 folding of polypeptide chains and the nature of the stable secondary structures have been well established. In proteins, sequence variability generated by the incorporation of 20 different genetically coded a-amino acids, which differ in the substituent at Ca, is the key to structural and functional diversity. b-Amino acids and higher backbone-homologated (u) residues are found in nature as constituents of peptide metabolites produced by micro-organisms. Poly-g-Dglutamate first reported from Bacillus anthracis (Hanby & Rydon 1946; Rydon 1964) has subsequently been shown to be produced by several species of bacillus (Ashiuchi & Misono 2002). Much of the early work on homopolypeptides of u-amino acids was stimulated by the interest in the structures of nylons (Glickson & Applequist 1971; Lovinger 1978; Fernandez-Santin et al. 1984; Munoz-Guerra et al. 1985; Puiggali & Munoz Guerra 1986; Lopez-Carrasquero et al. 1995; Bella et al. 1992; Navas et al. 1995; Aleman et al. 1997). More recently, the characterization of well-defined helical conformations in homo-oligomeric b-peptide sequences (Appella et al. 1996, 1997; Seebach et al. 1996a,b, 1997; 1998ac; Banerjee and Balaram 1997; Seebach & Matthews 1997b) has resulted in a sudden surge of interest in the conformational properties of peptides containing u-amino acids. Hybrid polypeptides, heteropolymers composed of diverse u-amino acids, are of special interest in attempts to mimic all a-peptide backbones, using sequences containing non-protein amino acids (Karle et al. 1997). This review surveys the conformational properties of hybrid peptides containing a-, b-, g- and d-amino acids as observed in crystal structures and advances the use of backbone torsion angles as convenient parameters for description of conformational variability. characterized by a 13-membered hydrogen bond (Huggins 1952a,b). This was quickly dismissed by Pauling, since the peptide units would have to deviate substantially from planarity to accommodate the 11-atom hydrogen-bonded ring (Pauling & Corey 1952). Current interest in the hydrogen-bonded structures of polypeptides chains stems from the realization that the repertoire of polypeptide chains can be vastly expanded when backbone-homologated amino acid residues are introduced (Gellman 1998; Cheng et al. 2001; Hill et al. 2001; Gademann et al. 2003; Lelias & Seebach 2004; Roy & Balaram 2004; Seebach et al. 2004, 2006; Kimmerlin & Seebach 2005). This overview considers recent research on hydrogen-bonded structures of peptides containing b-, g- and d-amino acids which have provided several examples of novel hydrogen-bonded patterns, hitherto unknown in all a-polypeptide structures. Naturally occurring polypeptide chains found in proteins are heteropolymers of a-amino acid residues linked together by peptide bonds. The stereochemistry of the polypeptide chain is best described by analysing the various orientations of two planar peptide units linked togeth (...truncated)