title: Effects of i and i+3 residue identity on cis-trans isomerism of the aromatic(i+1)-prolyl(i+2) amide bond: implications for type VI beta-turn formation.
abstract: Cis-trans isomerization of amide bonds plays critical roles in protein molecular recognition, protein folding, protein misfolding, and disease. Aromatic-proline sequences are particularly prone to exhibit cis amide bonds. The roles of residues adjacent to a tyrosine-proline residue pair on cis-trans isomerism were examined. A short series of peptides XYPZ was synthesized and cis-trans isomerism was analyzed. Based on these initial studies, a series of peptides XYPN, X = all 20 canonical amino acids, was synthesized and analyzed by NMR for i residue effects on cis-trans isomerization. The following effects were observed: (a) aromatic residues immediately preceding Tyr-Pro disfavor cis amide bonds, with K(trans/cis)= 5.7-8.0, W > Y > F; (b) proline residues preceding Tyr-Pro lead to multiple species, exhibiting cis-trans isomerization of either or both X-Pro amide bonds; and (c) other residues exhibit similar values of K(trans/cis) (= 2.9-4.2), with Thr and protonated His exhibiting the highest fraction cis. beta-Branched and short polar residues were somewhat more favorable in stabilizing the cis conformation. Phosphorylation of serine at the i position modestly increases the stability of the cis conformer. In addition, the effect of the i+3 residue was examined in a limited series of peptides TYPZ. NMR data indicated that aromatic residues, Pro, Asn, Ala, and Val at the i+3 residue all favor cis amide bonds, with aromatic residues and Asn favoring more compact phi at Tyr(cis) and Ala and Pro favoring more extended phi at Tyr(cis). D-Alanine at the i+3 position particularly disfavors cis amide bonds.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
authors.forename: Hai Yun
authors.initials: HY
authors.lastname: Meng
authors.forename: Krista M
authors.initials: KM
authors.lastname: Thomas
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Lee
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Zondlo
mesh_terms: D000577:Amides / Q000032:analysis / Q000737:chemistry*; D004151:Dipeptides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D000577:Amides; D004151:Dipeptides; D010455:Peptides; C120594:tyrosyl-proline; D011392:Proline