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Proline in protein structure


Proline is one of the nonessential amino acids, found in many proteins, especially collagen. Because the nitrogen atom of its amino group is part of a ring structure (making it a heterocyclic compound), its chemical properties differ from those of the other amino acids in proteins. It is used in biochemical, nutritional, and microbiological research and as a dietary supplement. 1. Properties in protein structure The distinctive cyclic structure of proline's side chain locks its backbone dihedral angle at approximately 60, giving proline an exceptional conformational rigidity compared to other amino acids. Hence, proline loses less conformational entropy upon folding, which may account for its higher prevalence in the proteins of thermophilic organisms. Proline acts as a structural disruptor in the middle of regular secondary structure elements such as alpha helices and beta sheets; however, proline is commonly found as the first residue of an alpha helix and also in the edge strands of beta sheets. Proline is also commonly found in turns, which may account for the curious fact that proline is usually solvent-exposed, despite having a completely aliphatic side chain. When proline is bound as an amide in a peptide bond, its nitrogen is not bound to any hydrogen, meaning it cannot act as a hydrogen bond donor, but can be a hydrogen bond acceptor. The distinct side chain/amine group interactions allow proline to aid in the formation of beta turns... Multiple prolines and/or hydroxyprolines in a row can create a polyproline helix, the predominant secondary structure in collagen. The hydroxylation of proline by prolyl hydroxylase (or other additions of electron-withdrawing substituents such as fluorine) increases the conformational stability of collagen significantly. Hence, the hydroxylation of proline is a critical biochemical process for maintaining the connective tissue of higher organisms. Severe diseases such as scurvy can result from defects in this hydroxylation, e.g., mutations in the enzyme prolyl hydroxylase or lack of the necessary ascorbate (vitamin C) cofactor. Sequences of proline and 2-aminoisobutyric acid (Aib) also form a helical turn structure. Peptide bond formation with incoming Pro-tRNAPro is considerably slower than with any other tRNAs, which is a general feature of N-alkylamino acids.[6] Peptide bond formation is also slow between an incoming tRNA and a chain ending in Proline; with the creation of Proline-Proline bonds slowest of all.

2. Cis-trans isomerization

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Peptide bonds to proline, and to other N-substituted amino acids (such as sarcosine), are able to populate both the cis and trans isomers. Most peptide bonds overwhelmingly adopt the trans isomer (typically 99.9% under unstrained conditions), chiefly because the amide hydrogen (trans isomer) offers less steric repulsion to the preceding \mathrm{C}^{\alpha} atom than does the following \mathrm{C}^{\alpha} atom (cis isomer). By contrast, the cis and trans isomers of the X-Pro peptide bond (where X represents any amino acid) both experience steric clashes with the neighboring substitution and are nearly equal energetically. Hence, the fraction of X-Pro peptide bonds in the cis isomer under unstrained conditions ranges from 10-40%; the fraction depends slightly on the preceding amino acid, with aromatic residues favoring the cis isomer slightly. From a kinetic standpoint, cis-trans proline isomerization is a very slow process that can impede the progress of protein folding by trapping one or more proline residues crucial for folding in the non-native isomer, especially when the native protein requires the cis isomer. This is because proline residues are exclusively synthesized in the ribosome as the trans isomer form. All organisms possess prolyl isomerase enzymes to catalyze this isomerization, and some bacteria have specialized prolyl isomerases associated with the ribosome. However, not all prolines are essential for folding, and protein folding may proceed at a normal rate despite having non-native conformers of many X-Pro peptide bonds.

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