Peptides extended conformation

While conformation II (Fig. 2.34) of Uke-y -amino acids is found in the 2.614-helical structure, conformation I, which similarly does not suffer from sy -pen-tane interaction, should be an appropriate alternative for the construction of sheet-like structures. However, sheet-like arrangement have not been reported so far for y-peptides composed of acyclic y " -amino acid residues. Nevertheless, other conformational biases (such as a,/9-unsaturation, cyclization between C(a) and C(y)) have been introduced into the y-amino acid backbone to restrict rotation around ethylene bonds and to promote extended conformation with formation of sheets in model peptides. Examples of such short chain y-peptides forming antiparallel (e.g. 152 [208]) and parallel (e.g. 153-155 [205, 208]) sheet-hke structures are shown in Fig. 2.38. 

The interaction between melittin (a 26 a.a. peptide that exhibits potent anti-microbial activity)90 92 and lipopolysaccharides (the major constituent of the outer membrane of the Gram-negative bacteria) has been studied by NMR. It was demonstrated that the C-terminus of melittin adopts a helical structure in the complex with LPS, while the Y-terminus appears in an extended conformation. STD experiments permitted to identify those residues of melittin in close proximity with LPS, which appeared to be located at the C-terminus and thus, engaged in the formation of helical structure. 

The characteristic properties of peptides result from the presence of a chain of several or many amide bonds. A first problem is that of numbering, and here Fig. 6.1 taken from the IUPAC-IUB rules may help. A second and major aspect of the structure of peptides is their conformational behavior. Three torsion angles exist in the backbone (Fig. 6.2). The dihedral angle co (omega) describes rotation about C-N,

rotation about N-C , and ip (psi) describes rotation about C -C. Fig. 6.2 represents a peptide in a fully extended conformation where these angles have a value of 180°. 

The third class of host defense peptides, the extended peptide class, is defined by the relative absence of a defined secondary structure. These peptides normally contain high proportions of amino acids such as histidine, tryptophan, or proline and tend to adopt an overall extended conformation upon interaction with hydrophobic environments. Examples of peptides belonging to the extended class include indolicidin, a bovine neutrophil peptide, and the porcine peptide fragment, tritpticin. These structures are stabilized by hydrogen bonding and van der Waals forces as a result of contact with lipids in contrast to the intramolecular stabilization forces found in the former peptide classes. 

Like the pentasaccharide, the octapeptide lies along the groove, roughly parallel to the Vh-Vl interface (Fig. 1A,B). One observes immediately that the peptide contacts some of the same areas of the binding site as the saccharide, but also extends into other areas of the site. The first four residues. Met Pl-Asp P2-Trp P3-Asn P4, adopt an extended conformation, and the last four residues. Met P5-His P6-Ala P7-Ala P8, form one turn of of-hefix. 

Although this methodology has been successfully used for a number of peptides, its efficacy for the cyclization of peptides with sterically hindered cyclization sites or difficult sequences of preferred extended conformation has not been investigated. 

By convention, the bond angles resulting from rotations at Ca are labeled (phi) for the N—C bond and i// (psi) for the C —C bond. Again by convention, both and extended conformation and all peptide groups are in the same plane (Fig. 4-2b). In principle, and i// can have any value between —180° and +180°, but many values are prohibited by steric interference between atoms in the polypeptide backbone and amino acid side chains. The conformation in which both and i// are 0° (Fig. 4-2c) is prohibited for this reason this conformation is used merely as a reference point for describing the angles of rotation. Allowed values for and i// are graphically revealed when i// is plotted versus in a Ramachandran plot (Fig. 4-3), introduced by G. N. Ramachandran. 

Figure 12-12 Formation of the oxyanion hole following cleavage of trypsinogen between Lys 15 and He 16. (A) Stereoscopic view. (B) Schematic representation. The newly created terminal -NH3+ of He 16 forms a hydrogen-bonded ion pair with the carboxylate of Asp 194. This breaks the hydrogen bond between Asp 194 and His 40 in trypsinogen, inducing the peptide segment 192-194 to shift from an extended conformation to a helical form in which the NH groups of Gly 193 and Ser 195 form the oxyanion hole. Notice that the positions and interactions of Asp 102, His 57, and Ser 195, the catalytic triad, are very little changed. From Birktoft et al.270...

The most stable elements of secondary structure of peptides and proteins are turns, helices, and extended conformations. Within each of these 3D-structures the most commonly found representatives are (3-turns,a-helices, and antiparallel (3-sheet conformations, respectively. y-TurnsJ5 310-helices, poly(Pro) helices, and (3-sheet conformations with a parallel strand arrangement have also been observed, although less frequently. Among the many types of (3-turns classified, type-I, type-II, and type-VI are the most usual, all being stabilized by an intramolecular i <— i+3 (backbone)C=0 -H—N(backbone) H-bond and characterized by either a tram (type-I and type-II) or a cis (type-VI) conformation about the internal peptide bond. In the type-I (3-turn a helical i+1 residue and a quasi-helical 1+2 residue are found, whereas in the type-II (3-turn the i+1 residue is semi-extended and the 1+2 residue is also quasi-helical but left-handed. This latter corner position may be easily occupied by the achiral Gly or a D-amino acid residue. 

Given the functional importance of at least part of the N-terminal extension, that closest to TM1, we decided to append the amino acid residues from Tyr-95 to Asn-75. The Protein Build command in the Biopolymer mode of Sybyl was used to attach this peptide epitope onto the protein in an extended conformation (with the Biopolymer Conformation Set command). Individual bonds were rotated to bring the N-terminal extension above the plane of the extracellular loops, thus allowing enough space for the agonist peptide SFLLRN to dock within the extracellular region between the loops and the N-terminus of the receptor. 

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