Preferred Backbone Conformations

Turning now to the chapters in this volume, a variety of complementary techniques and approaches have been used to characterize peptide and protein unfolding induced by temperature, pressure, and solvent. Our goal has been to assemble these complementary views within a single volume in order to develop a more complete picture of denatured peptides and proteins. The unifying observation in common to all chapters is the detection of preferred backbone conformations in experimentally accessible unfolded states. 

Although cyclization significantly reduces the accessible conformational space, cyclic peptides often maintain considerable flexibility. 36,37 The more the backbone prefers a single conformation, the more the side chains do the same, at least for the %rangle. The preferred backbone conformation is primarily determined by the tendency to minimize the allylic strain, 24,38 as shown in Scheme 2. If possible, the Ca-proton is syn to the carbonyl oxygen of... 

Furthermore, in flexible linear peptides the chemical shifts are typical of random structures similar to nonfolded proteins. Deviation from these random shifts sometimes identifies specific conformational preferences. NH-proton chemical shifts depend strongly on external influences (solvent, temperature, concentration, specific sequence). Random coil shifts for these protons correlate less well than chemical shifts of the a-protons or a-carbonsJ19-261 Not only are the shift differences of different heterotopic protons similar, but also those of diastereotopic P-protons. A preferred side-chain conformation is normally only found when there is also a preferred backbone conformation. 

The considerations discussed in detail in connection with the chemical, configurational, and conformational structure of polypropylene apply similarly to poly-1-butene and the higher poly-1-olefins. Also with poly-1-butene, the preferred backbone conformation is tgtg for the isotactic chain [37]. The various crystalline modifications correspond to greater or lesser deviations from these ideal chain conformations, coupled with variations in chain packing in the crystal lattice. 

Now that about 70 different disulfides have been seen in proteins and more than 20 of those have been refined at high resolution, it is possible to examine disulfide conformation in more detail, as it occurs in proteins. Many examples resemble the left-handed small-molecule structures extremely closely Fig. 46 shows the Cys-30-Cys-115 disulfide from egg white lysozyme. The x > Xs and x dihedral angles and the Ca-Ca distance can be almost exactly superimposed on Fig. 45 the only major difference is in Xi All of the small-molecule structures have Xi close to 60°. Figure 47 shows the Xi values for halfcystines found in proteins. The preferred value is -60° (which puts S-y trans to the peptide carbonyl), while 60° is quite rare since it produces unfavorable bumps between S-y and the main chain except with a few specific combinations of x value and backbone conformation. 

There is a correlation between the backbone conformations which commonly flank disulfides and the frequency with which disulfides occur in the different types of overall protein structure (see Section III,A for explanation of structure types), although it is unclear which preference is the cause and which the effect. There are very few disulfides in the antiparallel helical bundle proteins and none in proteins based on pure parallel /3 sheet (except for active-site disulfides such as in glutathione reductase). Antiparallel /3 sheet, mixed /8 sheet, and the miscellaneous a proteins have a half-cystine content of 0-5%. Small proteins with low secondary-structure content often have up to 15-20% half-cystine. Figure 52 shows the structure of insulin, one of the small proteins in which disulfides appear to play a major role in the organization and stability of the overall structure. 

Diastereomeric 1,3-amino alcohols 1 have been obtained by reduction of 4,5-dihydroisoxa-zoles350-353. 3C chemical shifts allow a stereochemical differentiation due to the formation of energetically preferred chelated conformations. Similar to /3-hydroxy carbonyl compounds and 1,3-diol derivatives, the chemical shifts of the backbone carbons are larger in the syn 1,3-amino alcohols than in the awn -isomers353. 

The other sub-cluster of H-L5-H exhibits a folded turn conformation with CO(i) to N-H(i+3) hydrogen bond in the linker region, quite different from the first sub-cluster. A third distinct sub-cluster has a helical conformation in the linker region. The E-L5-E linker has one large cluster and the second and third residues of the linker prefer mostly Or and the fourth residue conformations. The linker H-L5-E has a preference for main chain conformation to be cu for both the second and third residues and is non-specific for the other linker resicuies. Pro is found more often at the second position. The E-L5-H linker has no specific preference for main chain torsions at the first and fourth positions. However, L2 to L4 positions prefer Pe r r respectively. Our analyses on other linkers of less than eight residues are found to form similar clusters in the backbone conformational space. 

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