Non-proline cis peptide bonds in proteins.

In a non-redundant set of 571 proteins from the Brookhaven Protein Data Base, a total of 43 non-proline cis peptide bonds were identified. Average geometrical parameters of the well-defined cis peptide bonds in proteins determined at high resolution show that some parameters, most notably the bond angle at the amide bond nitrogen, deviate significantly from the corresponding one in the trans conformation. Since the same feature was observed in cis amide bonds in small molecule structures found in the Cambridge Structural Data Base, a new set of parameters for the refinement of protein structures containing non-Pro cis peptide bonds is proposed.A striking preference was observed for main-chain dihedral angles of the residues involved in cis peptide bonds. All residues N-terminal and most residues C-terminal to a non-Pro cis peptide bond (except Gly) are located in the beta-region of a phi/psi plot. Also, all of the few C-terminal residues (except Gly) located in the alpha-region of the phi/psi plot constitute the start of an alpha-helix in the respective structure. In the majority of cases, an intimate side-chain/side-chain interaction was observed between the flanking residues, often involving aromatic side-chains. Interestingly, most of the cases found occur in functionally important regions such as close to the active site of proteins. It is intriguing that many of the proteins containing non-proline cis peptide bonds are carbohydrate-binding or processing proteins. The occurrence of these unusual peptide bonds is significantly more frequent in structures determined at high resolution than in structures determined at medium and low resolution, suggesting that these bonds may be more abundant than previously thought. On the basis of our experience with the structure determination of coagulation factor XIII, we developed an algorithm for the identification of possibly overlooked cis peptide bonds that exploits the deviations of geometrical parameters from ideality. A few likely candidates based on our algorithm have been identified and are discussed.

[1]  G. N. Ramachandran,et al.  Conformation of polypeptides and proteins. , 1968, Advances in protein chemistry.

[2]  R. N. Kortzeborn,et al.  Results of Ab Initio Calculations on Formamide , 1970 .

[3]  M. Dreyfus,et al.  Molecular orbital calculations on the conformation of polypeptides and proteins. I. Preliminary investigations and simple dipeptides. , 1970, Journal of theoretical biology.

[4]  D. Pérahia,et al.  Molecular orbital calculations on the conformation of polypeptides and proteins. IV. The conformation of the prolyl and hydroxyprolyl residues. , 1970, Journal of theoretical biology.

[5]  Sture Forsén,et al.  The barrier to internal rotation in monosubstituted amides , 1971 .

[6]  M. Perricaudet,et al.  An abinitio quantum-mechanical investigation on the rotational isomerism in amides and esters. , 2009, International journal of peptide and protein research.

[7]  W. Steigemann,et al.  Two cis‐prolines in the Bence‐Jones protein Rei and the cis‐pro‐bend , 1974, FEBS letters.

[8]  H. Halvorson,et al.  Consideration of the Possibility that the slow step in protein denaturation reactions is due to cis-trans isomerism of proline residues. , 1975, Biochemistry.

[9]  K. Wüthrich,et al.  Nmr studies of the molecular conformations in the linear oligopeptides H‐(L‐Ala)n‐L‐Pro‐OH , 1976, Biopolymers.

[10]  G. N. Ramachandran,et al.  An explanation for the rare occurrence of cis peptide units in proteins and polypeptides. , 1976, Journal of molecular biology.

[11]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[12]  M. Karplus,et al.  Crystallographic R Factor Refinement by Molecular Dynamics , 1987, Science.

[13]  R. Wolfenden,et al.  Influences of solvent water on protein folding: free energies of solvation of cis and trans peptides are nearly identical. , 1988, Biochemistry.

[14]  William L. Jorgensen,et al.  Cis-trans energy difference for the peptide bond in the gas phase and in aqueous solution , 1988 .

[15]  P Argos,et al.  Oligopeptide biases in protein sequences and their use in predicting protein coding regions in nucleotide sequences , 1988, Proteins.

[16]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[17]  J E Wampler,et al.  Occurrence and role of cis peptide bonds in protein structures. , 1990, Journal of molecular biology.

[18]  J Moult,et al.  Analysis of the steric strain in the polypeptide backbone of protein molecules , 1991, Proteins.

[19]  R. Huber,et al.  Accurate Bond and Angle Parameters for X-ray Protein Structure Refinement , 1991 .

[20]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[21]  J. Thornton,et al.  Influence of proline residues on protein conformation. , 1991, Journal of molecular biology.

[22]  R. L. Baldwin,et al.  Cis proline mutants of ribonuclease A. I. thermal stability , 1992, Protein science : a publication of the Protein Society.

[23]  U. Hobohm,et al.  Selection of representative protein data sets , 1992, Protein science : a publication of the Protein Society.

[24]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[25]  C. Fierke,et al.  Structure and energetics of a non-proline cis-peptidyl linkage in a proline-202-->alanine carbonic anhydrase II variant. , 1993, Biochemistry.

[26]  U. Hahn,et al.  Stability and folding kinetics of ribonuclease T1 are strongly altered by the replacement of cis-proline 39 with alanine. , 1993, Journal of molecular biology.

[27]  L. Pedersen,et al.  Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  F. Schmid,et al.  A ribosome‐associated peptidyl‐prolyl cis/trans isomerase identified as the trigger factor. , 1995, The EMBO journal.

[29]  L. Pedersen,et al.  Structural evidence that the activation peptide is not released upon thrombin cleavage of factor XIII. , 1995, Thrombosis research.

[30]  L. Wyns,et al.  Sequential Structural Changes upon Zinc and Calcium Binding to Metal-free Concanavalin A* , 1996, The Journal of Biological Chemistry.

[31]  James Raftery,et al.  The structure of concanavalin A and its bound solvent determined with small-molecule accuracy at 0.94 [Aring ]resolution , 1997 .

[32]  Shmuel Pietrokovski,et al.  Breaking up is hard to do , 1998, Nature Structural Biology.

[33]  Ulf Reimer,et al.  Barriers to Rotation of Secondary Amide Peptide Bonds , 1998 .

[34]  H. Scheraga,et al.  Crystal structures of two mutants that have implications for the folding of bovine pancreatic ribonuclease A , 1998, Protein science : a publication of the Protein Society.

[35]  M. Weiss,et al.  Two non‐proline cis peptide bonds may be important for factor XIII function , 1998, FEBS letters.

[36]  T. Schindler,et al.  Prolyl isomerases do not catalyze isomerization of non-prolyl peptide bonds. , 1998, Biological chemistry.

[37]  M. Rapé,et al.  Recognition of protein substrates by the prolyl isomerase trigger factor is independent of proline residues. , 1998, Journal of molecular biology.

[38]  C Colovos,et al.  The 1.8 A crystal structure of the ycaC gene product from Escherichia coli reveals an octameric hydrolase of unknown specificity. , 1998, Structure.

[39]  Chris Sander,et al.  Who checks the checkers? Four validation tools applied to eight atomic resolution structures. EU 3-D Validation Network. , 1998, Journal of molecular biology.

[40]  A. Jabs,et al.  Peptide bonds revisited , 1998, Nature Structural &Molecular Biology.

[41]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..