Editing Proline (section)

==''Cis''–''trans'' isomerization==
[[Peptide bond]]s to proline, and to other ''N''-substituted amino acids (such as [[sarcosine]]), are able to populate both the ''[[Cis-trans isomerism|cis]]'' and ''[[trans isomer|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 C<sub>α</sub> atom than does the following C<sub>α</sub> 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 have a much lower energy difference.  Hence, the fraction of X-Pro peptide bonds in the ''cis'' isomer under unstrained conditions is significantly elevated, with ''cis'' fractions typically in the range of 3-10%.<ref name="alderson">{{cite journal | vauthors = Alderson TR, Lee JH, Charlier C, Ying J, Bax A | title = Propensity for ''cis''-Proline Formation in Unfolded Proteins | journal = ChemBioChem | volume = 19 | issue = 1 | pages = 37–42 | date = January 2018 | pmid = 29064600 | pmc = 5977977 | doi = 10.1002/cbic.201700548 | name-list-style = amp }}</ref> However, these values depend on the preceding amino acid, with Gly<ref name="sarkar">{{cite journal | vauthors = Sarkar SK, Young PE, Sullivan CE, Torchia DA | title = Detection of ''cis'' and ''trans'' X–Pro peptide bonds in proteins by 13C NMR: application to collagen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 15 | pages = 4800–4803 | date = August 1984 | pmid = 6589627 | pmc = 391578 | doi = 10.1073/pnas.81.15.4800 | name-list-style = amp | doi-access = free | bibcode = 1984PNAS...81.4800S }}</ref> and aromatic<ref name="thomas">{{cite journal | vauthors = Thomas KM, Naduthambi D, Zondlo NJ | title = Electronic control of amide ''cis''–''trans'' isomerism via the aromatic-prolyl interaction | journal = Journal of the American Chemical Society | volume = 128 | issue = 7 | pages = 2216–2217 | date = February 2006 | pmid = 16478167 | doi = 10.1021/ja057901y | name-list-style = amp }}</ref> residues yielding increased fractions of the ''cis'' isomer. ''Cis'' fractions up to 40% have been identified for aromatic–proline peptide bonds.<ref name="gustafson">{{cite journal | vauthors = Gustafson CL, Parsley NC, Asimgil H, Lee HW, Ahlbach C, Michael AK, Xu H, Williams OL, Davis TL, Liu AC, Partch CL | display-authors = 6 | title = A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms | journal = Molecular Cell | volume = 66 | issue = 4 | pages = 447–457.e7 | date = May 2017 | pmid = 28506462 | pmc = 5484534 | doi = 10.1016/j.molcel.2017.04.011 | name-list-style = amp }}</ref>

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]] [[enzyme]]s 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.