Secondary Structure Formation and CTI

The strong influence of proline on the conformation of the preceding residue reflects steric clashes involving the pyrrolidine ring. Of proline peptide bonds in secondary structures, 38% are found in loops or random coils, 26% appear in helices, 23% in turns, and 13% in /1-strands [93], 

Theoretical calculations showed that in a-helices trans proline peptide bonds can best be accepted up to the fourth position within the helix because there is neither a disruption of the hydrogen bonding network in this region nor does the bulk of the pyrrolidine ring seriously interfere with the regular helix geometry. Analyses of the Brookhaven database in 1991 also showed that the highest fre- 

In contrast to a-helices, /1-sheets do not involve interactions between amino acids close in sequence. Amino acids that interact within / -sheets are often found widely separated in the primary structure. Therefore, / -sheet formation needs structures that bring two polypeptide segments into close proximity. This is achieved via reverse turn structures [96]. Turns are aperiodic or nonrepetitive elements of secondary structure which mediate the folding of the polypeptide chain into a compact tertiary structure. Turns usually occur on the environment-exposed surface of proteins [97,98], Reverse turns play an important role in polypeptide function, both as elements of structure as well as modulators of bioactivity [99]. Among the reverse turns found in proteins the /1-turn is the most relevant [100]. /1-Turns comprise four amino acid residues (i to i+3) forming an almost complete 180° turn in the direction of the peptide chain [101,102]. 

Theoretical and experimental studies on the PP II structure showed that in an aqueous environment, water molecules form carbonyl-water-carbonyl H-bonds within the chain [117-119], which seems to be the driving force for favoring the trans conformation. Interchain water bridges in PP II are not possible because carbonyls in the PP II helix are sterically quite crowded by the neighboring atoms [120], The carbonyl-water-carbonyl clusters cannot be formed when the peptide adopts the PP I conformation. This explains why the PP I structure can be formed in hydrophobic solvents where this effect is negated. The PP I conformation has not yet been found in protein structures. 

An analysis of the HOMSTRAD database showed that the PP II conformation represents 3% of the all peptide conformations and even occurs in 1.3% of peptides when only helices consisting of more than three residues are considered [106]. Proline is greatly favored in PP II helices, whereas Gly and aromatic amino acids have low propensity for the PP II structure. It is worth noting that although Gly generally disfavors the PP II helix, it is common in collagen. Collagen consists 

---