The Peptide Unit

Figure 1.2 shows one way of dividing a polypeptide chain, the biochemist s way. There is, however, a different way to divide the main chain into repeating units that is preferable when we want to describe the structural properties of proteins. For this purpose it is more useful to divide the polypeptide chain into peptide units that go from one Ca atom to the next Ca atom (see Figure 1.5). Each C atom, except the first and the last, thus belongs to two such units. The reason for dividing the chain in this way is that all the atoms in such a unit are fixed in a plane with the bond lengths and bond angles very nearly the same in all units in all proteins. Note that the peptide units of the main chain do not involve the different side chains (Figure 1.5). We will use both of these alternative descriptions of polypeptide chains—the biochemical and the structural—and discuss proteins in terms of the sequence of different amino acids and the sequence of planar peptide units.

Since the peptide units are effectively rigid groups that are linked into a chain by covalent bonds at the Ca atoms, the only degrees of freedom they have are rotations around these bonds. Each unit can rotate around two such bonds the Ca-C and the N-Ca bonds (Figure 1.6). By convention the angle of rotation around the N-Ca bond is called phi (<[)) and the angle around the Ca-C bond from the same C atom is called psi (y). 

For proteins, the fragment is defined by the peptide unit convention as recommended by the International Union of Pure and Applied Chemistry, although the... 

The sum of the estimated average solvent-accessible surface areas, (ASA), for the peptide units (—CO—NH—) on either side of residue Xaa, plus the Ca of Xaa, in each peptide simulated are given in Table II. Also shown are the estimated PPII helix-forming propensities for each residue measured by Kelly et al. (2001) and A. L. Rucker, M. N. Campbell, and... 

The dipeptide model implies that the peptide unit is basically rigid and planar which is a good first order approximation, with characteristic deviations (M. W. MacArthur, 1996G). The effectiveness of the model and the significance of the main chain <)> and i / torsions for protein folding was first discovered by Sasisekharan (1962G), but the plots of peptide... 

A number of clinically useful drugs have been derivatized with a peptide pro-moiety with the view to improve pharmaceutical properties (e.g., solubility) and/or pharmacokinetic behavior (e.g., absorption or targeted delivery). In such cases, and in contrast to the peptides and derivatives and analogues discussed in Sect. 6.3- 6.6, the peptide unit is not part of the pharmacophore. 

The observed lengths in nanometers determined by X-ray diffraction measurements are given in Fig. 2-5 (top). The partial double-bond character of the C-N bond has important consequences. The peptide unit is nearly planar as is indicated by the dashed parallelogram in Fig. 2-5. 

More relevant for this section is the use of porphyrins as template for the construction of de novo metalloproteins. Indeed, the attachment of helical peptide units to these templates creates four-helix bundle structures that have been used as an artificial ion channel 2 or a hydroxylase enzymeJ33,34 In these cases, the peptide units were coupled to the template by using the HOSu or the TBTU methods. As illustrated in Scheme 10 starting from 33, formation of the tetrasuccimidyl ester 34 and attachment of the protected peptide unit 35 gives 36 and this is followed by deprotection to 37. 

In this section we consider peptide analogues containing the amide surrogates 1 to 11 (Scheme 1). These can be isosteric with the amide group in the sense that consecutive a-carbons are separated by three bonds, as in link 1, the (nitrono) peptides, and link 2, the [methyleneamino(hydroxy)] or (TV-hydroxy reduced amide) peptides. They also can be an N-modified amide, as in link 3, the (TV-hydroxy amide) peptides, and link 4, the (V-aminoamide) peptides. Elongation of the peptide unit by one covalent bond has been realized by the introduction of a heteroatom or a methylene into the backbone, as in link 5, the (hydrazide) peptides, link 6, the (amidoxy) peptides, link 7, the (oxomethyleneamino) peptides, link 8, the [(hydroxy)ethyleneamino] peptides, link 9, the (ethyleneamino) peptides, and link 10 the (oxime) peptides. Finally, insertion of an ethylenic bond (two covalent bonds) between the a-carbon and the carbonyl gives rise to link 11, the (but-2-enamide) or (vinylogous amide) peptides. 

Finally, Sherman and co-workers [39] recently reported the preparation of a four a-helix structure 46 by attaching the peptide units onto a synthetic bowl... 

Fig. 2. Electronic dipolar nature of the peptide unit. The numbers adjacent to each atom give the approximate fractional electronic charge attributed to each atom (in units of fundamental electronic charge). The magnitude of the dipole moment is 0.72 ek = 3.46 D.

Fortunately, CD spectroscopy is sensitive not only to the local chirality of the peptide unit, but it also reflects global chirality, that is, the way the chiral units are arranged in space. Therefore, CD can detect different secondary structures within the polypeptide chain. There are four main classes of secondary structures for proteins the a helix, the p sheet, the p turn, and the random coil. In addition, there are also other helix and turn variants which will be discussed. 

Figure 2.2. Diagram of a peptide unit the peptide unit formed by condensation polymerization is enclosed in a box that is within the plane of the paper. All atoms shown are to a first approximation found within the plane of the paper. The unit begins at the first alpha carbon, Ca, and ends at the second alpha carbon, Ca. Two angles (< >, i /) are sites of free rotation along the backbone of the chain and exist between adjacent peptide units. Both ( > and i are defined as positive for counterclockwise rotation looking from the nitrogen and carbonyl carbon positions towards the alpha carbon between these atoms.

From a structural viewpoint, a polypeptide is composed of planar peptide units as shown in Figure 2.8. The usefulness of considering the peptide unit as opposed to the amino acid is that the peptide unit is almost planar as opposed to the amino acid, which has atoms that are in more than one plane. To illustrate this point, the coordinates of atoms in the peptide unit are given in Table 2.2 and nonbonded atoms cannot be closer than the sum of the minimum atomic distances (Table 2.3). Note that all the atoms from the first alpha carbon (Ca) to the second alpha carbon do not have a z-coordinate. These coordinates come from X-ray diffraction studies on proteins and represent the average coordinates found among many pro-... 

Figure 2.17. Hydrogen bonding in antiparallel (3 sheet. Antiparallel hydrogen bonding between carbonyl and amide groups within the peptide unit stabilizes the (3 extended conformation.

The peptide unit so formed is a planar, rigid structure since there is restricted rotation about the C-N bond. This means that two isomers should be possible—a ds and a trans. 

It is found that nearly all the peptide units found in nature are trans. This is not surprising since the cis form is more crowded (a trans disubstituted double bond is lower in energy than a cis for the same reason). 

Highly accurate interatomic distances (ultimately 0.05 A) may be obtained from REDOR experiments [49], which are therefore an attractive tool for studies of hydrogen bonding. This technique has been used recently to characterise ex-helix structures in polypeptides by measuring 13C=0---H-15N hydrogen bond lengths [50]. The intrachain 13C- 15N interatomic distances, measured for a number of different samples, were found to be 4.5 0.1 A. This finding was used as evidence for the a-helix structure, which is consistent with the conformation dependent displacements of 13C chemical shifts of the Ca, Cp and carbonyl carbons of the peptide unit [51]. 

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