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Conformational landscape of substituted prolines

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Abstract

The cyclic side chain of the amino acid proline confers unique conformational restraints on its backbone and side chain dihedral angles. This affects two equilibria—one at the backbone (cis/trans) and the other at the side chain (endo/exo). Substitutions on the proline ring impose additional steric and stereoelectronic effects that can further modulate both these equilibria, which in turn can also affect the backbone dihedral angle (ϕ, ψ) preferences. In this review, we have explored the conformational landscape of several termini capped mono-(2-, 3-, 4-, and 5-) substituted proline derivatives in the Cambridge Structural Database, correlating observed conformations with the nature of substituents and deciphering the underlying interactions for the observed structural biases. The impact of incorporating these derivatives within model peptides and proteins are also discussed for selected cases. Several of these substituents have been used to introduce bioorthogonal functionality and modulate structure-specific ligand recognition or used as spectroscopic probes. The incorporation of these diversely applicable functional groups, coupled with their ability to define an amino acid conformation via stereoelectronic effects, have a broad appeal among chemical biologists, molecular biophysicists, and medicinal chemists.

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References

  • Anderson NG, Lust DA, Colapret KA et al (1996) Sulfonation with inversion by Mitsunobu reaction: an improvement on the original conditions. J Org Chem 61:7955–7958

    CAS  PubMed  Google Scholar 

  • Arndt H-D, Polborn K, Koert U (1997) Stereoselective synthesis of a terpyrrolidine unit, a potential building block for anion recognition. Tetrahedron Lett 38:3879–3882

    CAS  Google Scholar 

  • Azinas S, Colombo M, Barbiroli A et al (2011) D-strand perturbation and amyloid propensity in beta-2 microglobulin. FEBS J 278:2349–2358

    CAS  PubMed  Google Scholar 

  • Bartlett GJ, Choudhary A, Raines RT, Woolfson DN (2010) n→π* interactions in proteins. Nat Chem Biol 6:615–620

    CAS  PubMed  PubMed Central  Google Scholar 

  • Beatty JW, Douglas JJ, Miller R et al (2016) Photochemical perfluoroalkylation with pyridine N-oxides: mechanistic insights and performance on a kilogram scale. Chem 1:456–472

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berg RA, Prockop DJ (1973) The thermal transition of a non-hydroxylated form of collagen. Evidence for a role for hydroxyproline in stabilizing the triple-helix of collagen. Biochem Biophys Res Commun 52:115–120

    CAS  PubMed  Google Scholar 

  • Bhattacharyya R, Chakrabarti P (2003) Stereospecific interactions of proline residues in protein structures and complexes. J Mol Biol 331:925–940

    CAS  PubMed  Google Scholar 

  • Bisang C, Weber C, Inglis J et al (1995) Stabilization of type-I β-turn conformations in peptides containing the NPNA-repeat motif of the plasmodium falciparum circumsporozoite protein by substituting proline for (S)-α-methylproline. J Am Chem Soc 117:7904–7915

    CAS  Google Scholar 

  • Borgogno A, Ruzza P (2013) The impact of either 4-R-hydroxyproline or 4-R-fluoroproline on the conformation and SH3m-cort binding of HPK1 proline-rich peptide. Amino Acids 44:607–614

    CAS  PubMed  Google Scholar 

  • Bretscher LE, Jenkins CL, Taylor KM et al (2001) Conformational stability of collagen relies on a stereoelectronic effect. J Am Chem Soc 123:777–778

    CAS  PubMed  Google Scholar 

  • Cai M, Cai C, Mayorov AV et al (2004) Biological and conformational study of β-substituted prolines in MT-II template: steric effects leading to human MC5 receptor selectivity. J Pept Res 63:116–131

    CAS  PubMed  Google Scholar 

  • Chalker JM, Davis BG (2010) Chemical mutagenesis: selective post-expression interconversion of protein amino acid residues. Curr Opin Chem Biol 14:781–789

    CAS  PubMed  Google Scholar 

  • Chiang Y-C, Lin Y-J, Horng J-C (2009) Stereoelectronic effects on the transition barrier of polyproline conformational interconversion. Protein Sci 18:1967–1977

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chou PY, Fasman GD (1974) Prediction of protein conformation. Biochemistry 13:222–245

    CAS  PubMed  Google Scholar 

  • Clegg W, Deboves HJC, Elsegood MRJ (2003) 1-tert-butyl 2-methyl 4-(R)-hydroxypyrrolidine-1,2-(2S)-dicarboxylate. Acta Cryst E 59:o1987–o1989

    CAS  Google Scholar 

  • Cook WJ, Einspahr H, Trapane TL et al (1980) Crystal structure and conformation of the cyclic trimer of a repeat pentapeptide of elastin, cyclo-(L-valyl-L-prolylglycyl-L-valylglycyl)3. J Am Chem Soc 102:5502–5505

    CAS  Google Scholar 

  • Costantini NV, Ganguly HK, Martin MI et al (2019) The distinct conformational landscapes of 4S-substituted prolines that promote an endo ring pucker. Chem Eur J 25:11356–11364

    CAS  PubMed  Google Scholar 

  • Cowan PM, Mcgavin S, North AC (1955) The polypeptide chain configuration of collagen. Nature 176:1062–1064

    CAS  PubMed  Google Scholar 

  • Crespo MD, Rubini M (2011) Rational design of protein stability: effect of (2S,4R)-4-fluoroproline on the stability and folding pathway of ubiquitin. PLoS One 6:e19425

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crisma M, Toniolo C (2015) Helical screw-sense preferences of peptides based on chiral, Cα-tetrasubstituted α-amino acids. Pept Sci 104:46–64

    CAS  Google Scholar 

  • Dahanayake JN, Kasireddy C, Karnes JP, et al (2018) Chapter five-progress in our understanding of 19F chemical shifts. In: Webb GA (ed) Annual Reports on NMR Spectroscopy. Academic Press, pp 281–365

  • Dasgupta B, Chakrabarti P, Basu G (2007) Enhanced stability of cis Pro-Pro peptide bond in Pro-Pro-Phe sequence motif. FEBS Lett 581:4529–4532

    CAS  PubMed  Google Scholar 

  • Davies SG, Fletcher AM, Linsdall SM et al (2018) Asymmetric syntheses of (2R,3S)-3-hydroxyproline and (2S,3S)-3-hydroxyproline. Org Lett 20:4135–4139

    CAS  PubMed  Google Scholar 

  • De Poli M, Moretto A, Crisma M et al (2009) Is the backbone conformation of Cα-methyl proline restricted to a single region? Chem Eur J 15:8015–8025

    PubMed  Google Scholar 

  • DeRider ML, Wilkens SJ, Waddell MJ et al (2002) Collagen stability: insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations. J Am Chem Soc 124:2497–2505

    CAS  PubMed  Google Scholar 

  • Dorai K (2015) Chapter 4 - investigations of biomolecular conformation and dynamics using 19F NMR. In: ur-Rahman A, Choudhary MI (eds) Applications of NMR Spectroscopy: Volume 3. Bentham Science Publishers, pp 116–149

  • Drouillat B, Peggion C, Biondi B et al (2018) A novel peptide conformation: the γ-bend ribbon. Org Biomol Chem 16:7947–7958

    CAS  PubMed  Google Scholar 

  • Dunbrack RL, Karplus M (1994) Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains. Nat Struct Mol Biol 1:334–340

    CAS  Google Scholar 

  • Eyre DR, Weis M, Hudson DM et al (2011) A novel 3-Hydroxyproline (3Hyp)-rich motif marks the triple-helical C terminus of tendon type I collagen. J Biol Chem 286:7732–7736

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fatás P, Jiménez AI, Calaza MI, Cativiela C (2011) β-Phenylproline: the high β-turn forming propensity of proline combined with an aromatic side chain. Org Biomol Chem 10:640–651

    PubMed  Google Scholar 

  • Feng S, Chen JK, Yu H et al (1994) Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science 266:1241–1247

    CAS  PubMed  Google Scholar 

  • Fietzek PP, Kühn K (1975) Information contained in the amino acid sequence of the alpha1(I)-chain of collagen and its consequences upon the formation of the triple helix, of fibrils and crosslinks. Mol Cell Biochem 8:141–157

    CAS  PubMed  Google Scholar 

  • Fillon YA, Anderson JP, Chmielewski J (2005) Cell penetrating agents based on a polyproline helix scaffold. J Am Chem Soc 127:11798–11803

    CAS  PubMed  Google Scholar 

  • Fischer E (1902) Über eine neue Aminosäure aus Leim. Chem Ber 35:2660–2665

    CAS  Google Scholar 

  • Flamant-Robin C, Wang Q, Chiaroni A, Sasaki NA (2002) An efficient method for the stereoselective synthesis of cis-3-substituted prolines: conformationally constrained α-amino acids. Tetrahedron 58:10475–10484

    CAS  Google Scholar 

  • Flippen-Anderson JL, Gilardi R, Karle IL et al (1983) Crystal structures, molecular conformations, infrared spectra, and carbon-13 NMR spectra of methylproline peptides in the solid state. J Am Chem Soc 105:6609–6614

    CAS  Google Scholar 

  • Forbes CR, Pandey AK, Ganguly HK et al (2016) 4R- and 4S-iodophenyl hydroxyproline, 4R-pentynoyl hydroxyproline, and S-propargyl-4-thiolphenylalanine: conformationally biased and tunable amino acids for bioorthogonal reactions. Org Biomol Chem 14:2327–2346

    CAS  PubMed  PubMed Central  Google Scholar 

  • Foschi F, Landini D, Lupi V et al (2010) Enantioselective rearrangement of proline sulfonamides: an easy entry to enantiomerically pure α-aryl quaternary prolines. Chem Eur J 16:10667–10670

    CAS  PubMed  Google Scholar 

  • Ganguly HK, Kaur H, Basu G (2013) Local control of cis-peptidyl–prolyl bonds mediated by CH···π interactions: the Xaa-pro-Tyr motif. Biochemistry 52:6348–6357

    CAS  PubMed  Google Scholar 

  • Ganguly HK, Majumder B, Chattopadhyay S et al (2012) Direct evidence for CH···π interaction mediated stabilization of pro- cis pro bond in peptides with pro-pro-aromatic motifs. J Am Chem Soc 134:4661–4669

    CAS  PubMed  Google Scholar 

  • Ghosh M, Mallick A, Díaz DD (2014) Crystal structure of (2S, 4R)-2-benzyl 1-tert-butyl 4-(tosyloxy)pyrrolidine- 1,2-dicarboxylate, C24H29NO7S. Zeitschrift für Kristallographie - New Crystal Structures 227:361–362

    Google Scholar 

  • Gilchrist TL, Lemos A, Ottaway CJ (1997) Azabicyclo[3.2.0]heptan-7-ones (carbapenams) from pyrrole. J Chem Soc Perkin Trans 1:3005–3012

    Google Scholar 

  • Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45:106–124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grathwohl C, Wüthrich K (1976) The X-Pro peptide bond as an nmr probe for conformational studies of flexible linear peptides. Biopolymers 15:2025–2041

    CAS  PubMed  Google Scholar 

  • Hack V, Reuter C, Opitz R et al (2013) Efficient α-helix induction in a linear peptide chain by N-capping with a bridged-tricyclic diproline analogue. Angew Chem Int Ed 52:9539–9543

    CAS  Google Scholar 

  • Hetzel R, Wüthrich K (1979) Conformational energy studies of linear dipeptides H-X-L-Pro-OH. Biopolymers 18:2589–2606

    CAS  Google Scholar 

  • Ho BK, Brasseur R (2005) The Ramachandran plots of glycine and pre-proline. BMC Struct Biol 5:14

    PubMed  PubMed Central  Google Scholar 

  • Hodges JA, Raines RT (2003) Stereoelectronic effects on collagen stability: the dichotomy of 4-fluoroproline diastereomers. J Am Chem Soc 125:9262–9263

    CAS  PubMed  Google Scholar 

  • Holmgren SK, Bretscher LE, Taylor KM, Raines RT (1999) A hyperstable collagen mimic. Chem Biol 6:63–70

    CAS  PubMed  Google Scholar 

  • Holzberger B, Marx A (2010) Replacing 32 Proline residues by a noncanonical amino acid results in a highly active DNA polymerase. J Am Chem Soc 132:15708–15713

    CAS  PubMed  Google Scholar 

  • Holzberger B, Obeid S, Welte W et al (2012) Structural insights into the potential of 4-fluoroproline to modulate biophysical properties of proteins. Chem Sci 3:2924–2931

    CAS  Google Scholar 

  • Horng J-C, Raines RT (2006) Stereoelectronic effects on polyproline conformation. Protein Sci 15:74–83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hospital M, Courseille C, Leroy F, Roques BP (1979) The role of water in the crystal structure of N-acetyl-L-4-hydroxyproline. Biopolymers 18:1141–1148

    CAS  Google Scholar 

  • Hsu W-L, Shih T-C, Horng J-C (2015) Folding stability modulation of the villin headpiece helical subdomain by 4-fluorophenylalanine and 4-methylphenylalanine. Biopolymers 103:627–637

    CAS  PubMed  Google Scholar 

  • Huang K-Y, Horng J-C (2015) Modulating the affinities of phosphopeptides for the human Pin1 WW domain using 4-substituted proline derivatives. Biochemistry 54:6186–6194

    CAS  PubMed  Google Scholar 

  • Hudson DM, Eyre DR (2013) Collagen prolyl 3-hydroxylation: a major role for a minor post-translational modification? Connect Tissue Res 54:245–251

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hudson DM, Kim LS, Weis M et al (2012) Peptidyl 3-hydroxyproline binding properties of type I collagen suggest a function in fibril supramolecular assembly. Biochemistry 51:2417–2424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hudson DM, Werther R, Weis M et al (2014) Evolutionary origins of C-terminal (GPP) n 3-hydroxyproline formation in vertebrate tendon collagen. PLoS One 9:e93467

    PubMed  PubMed Central  Google Scholar 

  • Hussaini SR, Moloney MG (2003) 2,5-disubstituted pyrrolidines: versatile regioselective and diastereoselective synthesis by enamine reduction and subsequent alkylation. Org Biomol Chem 1:1838–1841

    CAS  PubMed  Google Scholar 

  • Huy P, Neudörfl J-M, Schmalz H-G (2011) A practical synthesis of trans-3-substituted proline derivatives through 1,4-addition. Org Lett 13:216–219

    CAS  PubMed  Google Scholar 

  • Jäger M, Dendle M, Kelly JW (2009) Sequence determinants of thermodynamic stability in a WW domain—an all-β-sheet protein. Protein Sci 18:1806–1813

    PubMed  PubMed Central  Google Scholar 

  • Jenkins CL, Bretscher LE, Guzei IA, Raines RT (2003) Effect of 3-hydroxyproline residues on collagen stability. J Am Chem Soc 125:6422–6427

    CAS  PubMed  Google Scholar 

  • Jenkins CL, Raines RT (2002) Insights on the conformational stability of collagen. Nat Prod Rep 19:49–59

    CAS  PubMed  Google Scholar 

  • Jones RCF, Howard KJ, Snaith JS et al (2011) An enantioselective route to pyrrolidines: removal of the chiral template from homochiral pyrroloimidazoles. Tetrahedron 67:8925–8936

    CAS  Google Scholar 

  • Juvvadi P, Dooley DJ, Humblet CC et al (1992) Bradykinin and angiotensin II analogs containing a conformationally constrained proline analog. Int J Pept Protein Res 40:163–170

    CAS  PubMed  Google Scholar 

  • Kantharaju RS, Raghavender US et al (2009) Conformations of heterochiral and homochiral proline-pseudoproline segments in peptides: context dependent cis–trans peptide bond isomerization. Pept Sci 92:405–416

    CAS  Google Scholar 

  • Kato Y (2015) An engineered bacterium auxotrophic for an unnatural amino acid: a novel biological containment system. PeerJ 3:e1247

    PubMed  PubMed Central  Google Scholar 

  • Kang YK, Park HS (2014) Conformational preferences of the 2-methylproline residue and its role in stabilizing β-turn and polyproline II structures of peptides. New J Chem 38:2831–2840

    CAS  Google Scholar 

  • Kemmink J, Creighton TE (1993) Local conformations of peptides representing the entire sequence of bovine pancreatic trypsin inhibitor and their roles in folding. J Mol Biol 234:861–878

    CAS  PubMed  Google Scholar 

  • Kemmink J, Creighton TE (1995) The physical properties of local interactions of tyrosine residues in peptides and unfolded proteins. J Mol Biol 245:251–260

    CAS  PubMed  Google Scholar 

  • Kim W, George A, Evans M, Conticello VP (2004) Cotranslational incorporation of a structurally diverse series of proline analogues in an Escherichia coli expression system. ChemBioChem 5:928–936

    CAS  PubMed  Google Scholar 

  • Kim W, Hardcastle KI, Conticello VP (2006) Fluoroproline Flip-flop: regiochemical reversal of a stereoelectronic effect on peptide and protein structures. Angew Chem Int Ed 45:8141–8145

    CAS  Google Scholar 

  • Kim W, McMillan RA, Snyder JP, Conticello VP (2005) A stereoelectronic effect on turn formation due to proline substitution in elastin-mimetic polypeptides. J Am Chem Soc 127:18121–18132

    CAS  PubMed  Google Scholar 

  • Kobayashi S, Chikushi A, Tougu S et al (2004) Membrane translocation mechanism of the antimicrobial peptide Buforin 2. Biochemistry 43:15610–15616

    CAS  PubMed  Google Scholar 

  • Kotch FW, Guzei IA, Raines RT (2008) Stabilization of the collagen triple helix by O-methylation of hydroxyproline residues. J Am Chem Soc 130:2952–2953

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kubyshkin V (2019) Stabilization of the triple helix in collagen mimicking peptides. Org Biomol Chem 17:8031–8047

    CAS  PubMed  Google Scholar 

  • Kubyshkin V, Budisa N (2017) Amide rotation trajectories probed by symmetry. Org Biomol Chem 15:6764–6772

    CAS  PubMed  Google Scholar 

  • Kubyshkin V, Pridma S, Budisa N (2018) Comparative effects of trifluoromethyl- and methyl-group substitutions in proline. New J Chem 42:13461–13470

    CAS  Google Scholar 

  • Kümin M, Sonntag L-S, Wennemers H (2007) Azidoproline containing helices: stabilization of the polyproline II structure by a functionalizable group. J Am Chem Soc 129:466–467

    PubMed  Google Scholar 

  • Kurtz J, Berger A, Katchalski E (1956) Mutarotation of poly-L-proline. Nature 178:1066–1067

    CAS  Google Scholar 

  • Lewis PN, Momany FA, Scheraga HA (1973) Chain reversals in proteins. Biochimica et Biophysica Acta (BBA) - Protein Structure 303:211–229

    CAS  Google Scholar 

  • Lübben J, Volkmann C, Grabowsky S et al (2014) On the temperature dependence of H-Uiso in the riding hydrogen model. Acta Cryst A 70:309–316

    Google Scholar 

  • Lummis SCR, Beene DL, Lee LW et al (2005) Cis–trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 438:248–252

    CAS  PubMed  Google Scholar 

  • Lynch VM, Hulme C, Magnus P, Davis BE (1995) Novel 2- and 5-Azido-N-(diphenylcarbamoyl) proline methyl esters. Examples of a novel proline oxidation. Acta Cryst C 51:2598–2601

    Google Scholar 

  • MacArthur MW, Thornton JM (1991) Influence of proline residues on protein conformation. J Mol Biol 218:397–412

    CAS  PubMed  Google Scholar 

  • Masumi F, Takeuchi H, Kondo S et al (1982) Synthesis of L-tryptophan from L-glutamic acid. Chemical & Pharmaceutical Bulletin 30:3831–3833

    CAS  Google Scholar 

  • Matsumura Y, Ogura K, Kouchi Y et al (2006) New efficient organic activators for highly enantioselective reduction of aromatic ketones by trichlorosilane. Org Lett 8:3789–3792

    CAS  PubMed  Google Scholar 

  • Meng HY, Thomas KM, Lee AE, Zondlo NJ (2006) Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatici+1–prolyli+2 amide bond: implications for type VI β-turn formation. Pept Sci 84:192–204

    CAS  Google Scholar 

  • Moloney MG, Panchal T, Pike R (2006) trans-2,5-disubstituted pyrrolidines: rapid stereocontrolled access from sulfones. Org Biomol Chem 4:3894–3897

    CAS  PubMed  Google Scholar 

  • Mooney SD, Kollman PA, Klein TE (2002) Conformational preferences of substituted prolines in the collagen triple helix. Biopolymers 64:63–71

    CAS  PubMed  Google Scholar 

  • Moretto A, Terrenzani F, Crisma M et al (2008) Cα-methyl proline: a unique example of split personality. Biopolymers 89:465–470

    CAS  PubMed  Google Scholar 

  • Moroder L, Budisa N (2010) Synthetic biology of protein folding. ChemPhysChem 11:1181–1187

    CAS  PubMed  Google Scholar 

  • Mortenson DE, Kreitler DF, Thomas NC et al (2018) Evaluation of β-amino acid replacements in protein loops: effects on conformational stability and structure. ChemBioChem 19:604–612

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mulzer J, Schülzchen F, Bats J-W (2000) Rigid dipeptide mimetics. Stereocontrolled synthesis of all eight stereoisomers of 2-Oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid ester. Tetrahedron 56:4289–4298

    CAS  Google Scholar 

  • Mykhailiuk PK, Kubyshkin V, Bach T, Budisa N (2017) Peptidyl-prolyl model study: how does the electronic effect influence the amide bond conformation? J Org Chem 82:8831–8841

    CAS  PubMed  Google Scholar 

  • Naduthambi D, Zondlo NJ (2006) Stereoelectronic tuning of the structure and stability of the Trp cage miniprotein. J Am Chem Soc 128:12430–12431

    CAS  PubMed  Google Scholar 

  • Nanzer AP, Torda AE, Bisang C, et al (1997) Dynamical studies of peptide motifs in the plasmodium falciparum circumsporozoite surface protein by restrained and unrestrained MD simulations11Edited by R. Huber Journal of Molecular Biology 267:1012–1025

    CAS  PubMed  Google Scholar 

  • Nardi F, Kemmink J, Sattler M, Wade RC (2000) The cisproline(i - 1)-aromatic(i) interaction: folding of the Ala-cisPro-Tyr peptide characterized by NMR and theoretical approaches. J Biomol NMR 17:63–77

    CAS  PubMed  Google Scholar 

  • Newberry RW, Raines RT (2017) The n→π* interaction. Acc Chem Res 50:1838–1846

    CAS  PubMed  PubMed Central  Google Scholar 

  • O’Hagan D, Bilton C, Howard JAK et al (2000) The preferred conformation of N-β-fluoroethylamides. Observation of the fluorine amide gauche effect. J Chem Soc Perkin Trans 2:605–607

    Google Scholar 

  • Onomura O, Kirira PG, Tanaka T et al (2008) Diastereoselective arylation of l-proline derivatives at the 5-position. Tetrahedron 64:7498–7503

    CAS  Google Scholar 

  • Pal D, Chakrabarti P (1999) Cis peptide bonds in proteins: residues involved, their conformations, interactions and locations. J Mol Biol 294:271–288

    CAS  PubMed  Google Scholar 

  • Panasik N, Eberhardt ES, Edison AS et al (1994) Inductive effects on the structure of proline residues. Int J Pept Protein Res 44:262–269

    CAS  PubMed  Google Scholar 

  • Pandey AK, Naduthambi D, Thomas KM, Zondlo NJ (2013) Proline editing: a general and practical approach to the synthesis of functionally and structurally diverse peptides. Analysis of steric versus stereoelectronic effects of 4-substituted prolines on conformation within peptides. J Am Chem Soc 135:4333–4363

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pandey AK, Yap GPA, Zondlo NJ (2014) (2S,4R)-4-hydroxyproline(4-nitrobenzoate): strong induction of stereoelectronic effects via a readily synthesized Proline derivative. Crystallographic observation of a correlation between torsion angle and bond length in a hyperconjugative interaction. J Org Chem 79:4174–4179

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park HS, Byun BJ, Motooka D et al (2012) Conformational preferences of 4-chloroproline residues. Biopolymers 97:629–641

    CAS  PubMed  Google Scholar 

  • Pierson NA, Chen L, Russell DH, Clemmer DE (2013) Cis–trans isomerizations of proline residues are key to bradykinin conformations. J Am Chem Soc 135:3186–3192

    CAS  PubMed  PubMed Central  Google Scholar 

  • Plimmer RHA (1912) The chemical constitution of the proteins: analysis. Longmans, Green & Company

    Google Scholar 

  • Polindara-García LA, Miranda LD (2012) Two-step synthesis of 2,3-dihydropyrroles via a formal 5-endo cycloisomerization of Ugi 4-CR/propargyl adducts. Org Lett 14:5408–5411

    PubMed  Google Scholar 

  • Rajalakshmi P, Srinivasan N, Krishnakumar RV et al (2013) N-tert-but­oxy­carbonyl-α-(2-fluoro­benzyl)-l-proline. Acta Cryst E 69:o1297–o1297

    CAS  Google Scholar 

  • Ramachandran GN, Mitra AK (1976) An explanation for the rare occurrence of cis peptide units in proteins and polypeptides. J Mol Biol 107:85–92

    CAS  PubMed  Google Scholar 

  • Ramachandran GN, Ramakrishnan C, Sasisekharan V (1963) Stereochemistry of polypeptide chain configurations. J Mol Biol 7:95–99

    CAS  PubMed  Google Scholar 

  • Ramachandran GN, Sasisekharan V (1968) Conformation of polypeptides and proteins* In: Anfinsen CB, Anson ML, Edsall JT, Richards FM (eds) Advances in Protein Chemistry. Academic Press, pp 283–437

  • Reimer U, Scherer G, Drewello M, et al (1998) Side-chain effects on peptidyl-prolyl cis/trans isomerisation11Edited by A. R Fersht Journal of Molecular Biology 279:449–460

    CAS  PubMed  Google Scholar 

  • Reuter C, Huy P, Neudörfl J-M et al (2011) Exercises in pyrrolidine chemistry: gram scale synthesis of a pro–pro dipeptide mimetic with a polyproline type II helix conformation. Chem Eur J 17:12037–12044

    CAS  PubMed  Google Scholar 

  • Reuter C, Opitz R, Soicke A et al (2015) Design and stereoselective synthesis of ProM-2: a spirocyclic diproline mimetic with polyproline type II (PPII) helix conformation. Chem Eur J 21:8464–8470

    CAS  PubMed  Google Scholar 

  • Richardson JS (1981) The anatomy and taxonomy of protein structure. Adv Protein Chem 34:167–339

    CAS  PubMed  Google Scholar 

  • Rodríguez I, Calaza MI, Jiménez AI, Cativiela C (2015) Synthesis of enantiomerically pure δ-benzylproline derivatives. New J Chem 39:3310–3318

    Google Scholar 

  • Rose-Sperling D, Tran MA, Lauth LM et al (2019) 19F NMR as a versatile tool to study membrane protein structure and dynamics. Biol Chem 400:1277–1288

    CAS  PubMed  Google Scholar 

  • Rubini C, Ruzza P, Spaller MR et al (2010) Recognition of lysine-rich peptide ligands by murine cortactin SH3 domain: CD, ITC, and NMR studies. Pept Sci 94:298–306

    CAS  Google Scholar 

  • Rubini M, Schärer MA, Capitani G, Glockshuber R (2013) (4R)- and (4S)-fluoroproline in the conserved cis-prolyl peptide bond of the thioredoxin fold: tertiary structure context dictates ring puckering. ChemBioChem 14:1053–1057

    CAS  PubMed  Google Scholar 

  • Salih N, Adams H, Jackson RFW (2016) Synthesis of ω-Oxo amino acids and trans-5-substituted proline derivatives using cross-metathesis of unsaturated amino acids. J Org Chem 81:8386–8393

    CAS  PubMed  Google Scholar 

  • Sasisekharan V, Ramachandran GN (1957) Studies on collagen. Proc Indian Acad Sci 45:363–376

    Google Scholar 

  • Schnitzer T, Wennemers H (2018) Effect of γ-substituted proline derivatives on the performance of the peptidic catalyst H-dPro-pro-Glu-NH2. Synthesis 50:4377–4382

    CAS  Google Scholar 

  • Sem DS, Baker BL, Victoria EJ et al (1998) Structural characterization and optimization of antibody-selected phage library mimotopes of an antigen associated with autoimmune recurrent thrombosis. Biochemistry 37:16069–16081

    CAS  PubMed  Google Scholar 

  • Shoulders MD, Guzei IA, Raines RT (2008) 4-Chloroprolines: synthesis, conformational analysis, and effect on the collagen triple helix. Biopolymers 89:443–454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoulders MD, Hodges JA, Raines RT (2006) Reciprocity of steric and stereoelectronic effects in the collagen triple helix. J Am Chem Soc 128:8112–8113

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoulders MD, Kamer KJ, Raines RT (2009) Origin of the stability conferred upon collagen by fluorination. Bioorg Med Chem Lett 19:3859–3862

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoulders MD, Kotch FW, Choudhary A et al (2010) The aberrance of the 4S diastereomer of 4-hydroxyproline. J Am Chem Soc 132:10857–10865

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoulders MD, Raines RT (2009a) Modulating collagen triple-helix stability with 4-chloro, 4-fluoro, and 4-methylprolines. Adv Exp Med Biol 611:251

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shoulders MD, Raines RT (2009b) Collagen structure and stability. Annu Rev Biochem 78:929–958

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siebler C, Trapp N, Wennemers H (2015) Crystal structure of (4S)-aminoproline: conformational insight into a pH-responsive proline derivative. J Pept Sci 21:208–211

    CAS  PubMed  Google Scholar 

  • Smolskaya S, Andreev YA (2019) Site-specific incorporation of unnatural amino acids into Escherichia coli recombinant protein: methodology development and recent achievement. Biomolecules 9:pii: E255

    CAS  PubMed Central  Google Scholar 

  • Soave R, Roversi P, Destro R (1997) Two 1,5-disubstituted proline esters. Acta Cryst C 53:933–936

    Google Scholar 

  • Sonntag L-S, Schweizer S, Ochsenfeld C, Wennemers H (2006) The “azido gauche effect”implications for the conformation of azidoprolines. J Am Chem Soc 128:14697–14703

    CAS  PubMed  Google Scholar 

  • Steiner T, Hess P, Bae JH et al (2008) Synthetic biology of proteins: tuning GFPs folding and stability with fluoroproline. PLoS One 3:e1680

    PubMed  PubMed Central  Google Scholar 

  • Szcześniak P, Maziarz E, Stecko S, Furman B (2015) Synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics via one-pot sequential lactam reduction/Joullié–Ugi reaction. J Org Chem 80:3621–3633

    PubMed  Google Scholar 

  • Tamaki M, Han G, Hruby VJ (2001) Synthesis of 4-cis-phenyl-l-proline via hydrogenolysis. J Org Chem 66:3593–3596

    CAS  PubMed  Google Scholar 

  • Tamazyan R, Ayvazyan A, Martirosyan A et al (2008) 1-(4-Bromo­benzo­yl)-2-phenyl­pyrrolidine-2-carboxamide. Acta Cryst E 64:o580–o580

    CAS  Google Scholar 

  • Tamazyan R, Karapetyan H, Martirisyan A et al (2004) 1,2,5-substituted derivatives of 2-phenyl­pyrrolidine. Acta Cryst C 60:o390–o392

    Google Scholar 

  • Tamazyan R, Karapetyan H, Martirosyan A et al (2002) 1-substituted derivatives of 2-phenylpyrrolidine-2-carboxamide. Acta Cryst C 58:o386–o388

    Google Scholar 

  • Tang H-C, Lin Y-J, Horng J-C (2014) Modulating the folding stability and ligand binding affinity of Pin1 WW domain by proline ring puckering. Proteins: Structure, Function, and Bioinformatics 82:67–76

    CAS  Google Scholar 

  • Thomas CA, Talaty ER, Bann JG (2009) 3S-Fluoroproline as a probe to monitor proline isomerization during protein folding by 19F-NMR. Chem Commun:3366–3368

  • Thomas KM, Naduthambi D, Tririya G, Zondlo NJ (2005) Proline editing: a divergent strategy for the synthesis of conformationally diverse peptides. Org Lett 7:2397–2400

    CAS  PubMed  Google Scholar 

  • Thomas KM, Naduthambi D, Zondlo NJ (2006) Electronic control of amide cis−trans isomerism via the aromatic−prolyl interaction. J Am Chem Soc 128:2216–2217

    CAS  PubMed  Google Scholar 

  • Tolmachova NA, Kondratov IS, Dolovanyuk VG et al (2018) Synthesis of new fluorinated proline analogues from polyfluoroalkyl β-ketoacetals and ethyl isocyanoacetate. Chem Commun 54:9683–9686

    CAS  Google Scholar 

  • Toniolo C (1989) Structure of conformationally constrained peptides: from model compounds to bioactive peptides. Biopolymers 28:247–257

    CAS  PubMed  Google Scholar 

  • Torbeev V, Ebert M-O, Dolenc J, Hilvert D (2015) Substitution of proline32 by α-methylproline preorganizes β2-microglobulin for oligomerization but not for aggregation into amyloids. J Am Chem Soc 137:2524–2535

    CAS  PubMed  Google Scholar 

  • Torbeev VY, Fumi E, Ebert M-O et al (2012) Cis-trans peptide-bond isomerization in α-methylproline derivatives. Helvetica Chimica Acta 95:2411–2420

    CAS  Google Scholar 

  • Tran JA, Chen CW, Tucci FC et al (2008) Syntheses of tetrahydrothiophenes and tetrahydrofurans and studies of their derivatives as melanocortin-4 receptor ligands. Bioorg Med Chem Lett 18:1124–1130

    CAS  PubMed  Google Scholar 

  • Traub W, Shmueli U (1963) Structure of poly- L -proline I. Nature 198:1165–1166

    Google Scholar 

  • Tressler CM, Zondlo NJ (2014) (2S,4R)- and (2S,4S)-perfluoro-tert-butyl 4-hydroxyproline: two conformationally distinct proline amino acids for sensitive application in 19F NMR. J Org Chem 79:5880–5886

    CAS  PubMed  PubMed Central  Google Scholar 

  • Urry DW, Luan C-H, Harris CM, Parker TM (1997) Protein-based materials with a profound range of properties and applications: the elastin ΔTt hydrophobic paradigm. Protein-Based Materials 133–178

  • Urry DW, Shaw RG, Prasad KU (1985) Polypentapeptide of elastin: temperature dependence of ellipticity and correlation with elastomeric force. Biochem Biophys Res Commun 130:50–57

    CAS  PubMed  Google Scholar 

  • Valle JRD, Goodman M (2002) Stereoselective synthesis of Boc-protected cis and trans-4-trifluoromethylprolines by asymmetric hydrogenation reactions. Angew Chem Int Ed 41:1600–1602

    Google Scholar 

  • Venkatachalam CM (1968) Stereochemical criteria for polypeptides and proteins. V Conformation of a system of three linked peptide units Biopolymers 6:1425–1436

    CAS  PubMed  Google Scholar 

  • Verhoork SJM, Killoran PM, Coxon CR (2018) Fluorinated prolines as conformational tools and reporters for peptide and protein chemistry. Biochemistry 57:6132–6143

    CAS  PubMed  Google Scholar 

  • Wals K, Ovaa H (2014) Unnatural amino acid incorporation in E. coli: current and future applications in the design of therapeutic proteins. Front Chem 2:15

  • Webb TR, Eigenbrot C (1991) Conformationally restricted arginine analogs. J Org Chem 56:3009–3016

    CAS  Google Scholar 

  • Weis MA, Hudson DM, Kim L et al (2010) Location of 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly. J Biol Chem 285:2580–2590

    CAS  PubMed  Google Scholar 

  • Welsh JH, Zerbe O, von Philipsborn W, Robinson JA (1992) β-Turns induced in bradykinin by (S)-α-methylproline. FEBS Lett 297:216–220

    CAS  PubMed  Google Scholar 

  • Wenzell NA, Ganguly HK, Pandey AK et al (2019) Electronic and steric control of n→π* interactions: stabilization of the α-helix conformation without a hydrogen bond. ChemBioChem 20:963–967

    CAS  PubMed  Google Scholar 

  • Wilmot CM, Thornton JM (1988) Analysis and prediction of the different types of β-turn in proteins. J Mol Biol 203:221–232

    CAS  PubMed  Google Scholar 

  • Wu W-J, Raleigh DP (1998) Local control of peptide conformation: stabilization of cis proline peptide bonds by aromatic proline interactions. Biopolymers 45:381–394

    CAS  PubMed  Google Scholar 

  • Yao J, Feher VA, Fabiola Espejo B et al (1994) Stabilization of a type VI turn in a family of linear peptides in water solution. J Mol Biol 243:736–753

    CAS  PubMed  Google Scholar 

  • Zheng T-Y, Lin Y-J, Horng J-C (2010) Thermodynamic consequences of incorporating 4-substituted proline derivatives into a small helical protein. Biochemistry 49:4255–4263

    CAS  PubMed  Google Scholar 

  • Zhong H, Carlson HA (2006) Conformational studies of polyprolines. J Chem Theory Comput 2:342–353

    CAS  PubMed  Google Scholar 

  • Zondlo NJ (2010) Fold globally, bond locally. Nat Chem Biol 6:567–568

    CAS  PubMed  Google Scholar 

  • Zondlo NJ (2013) Aromatic–proline interactions: electronically tunable CH/π interactions. Acc Chem Res 46:1039–1049

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by an intramural grant to GB from Bose Institute.

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  1. Department of Biophysics, Bose Institute, P-1/12 CIT scheme VII M, Kolkata, 700054, India

    Himal Kanti Ganguly & Gautam Basu

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  1. Himal Kanti Ganguly
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  2. Gautam Basu
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HKG performed the literature search. HKG and GB analyzed the data and wrote the review.

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Correspondence to Himal Kanti Ganguly or Gautam Basu.

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Ganguly, H.K., Basu, G. Conformational landscape of substituted prolines. Biophys Rev 12, 25–39 (2020). https://doi.org/10.1007/s12551-020-00621-8

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