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Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy

Walse, B LU ; Ullner, M LU ; Lindbladh, C; Bülow, L LU ; Drakenberg, T LU and Teleman, O (1996) In Journal of Computer-Aided Molecular Design 10(1). p.11-22
Abstract

We report the design of a cyclic, eight-residue peptide that possesses the catalytic triad residues of the serine proteases. A manually built model has been relaxed by 0.3 ns of molecular dynamics simulation at room temperature, during which no major changes occurred in the peptide. The molecule has been synthesised and purified. Two-dimensional NMR spectroscopy provided 35 distance and 7 torsion angle constraints, which were used to determine the three-dimensional structure. The experimental conformation agrees with the predicted one at the beta-turn, but deviates in the arrangement of the disulphide bridge that closes the backbone to a ring. A 1.2 ns simulation at 600 K provided extended sampling of conformation space. The disulphide... (More)

We report the design of a cyclic, eight-residue peptide that possesses the catalytic triad residues of the serine proteases. A manually built model has been relaxed by 0.3 ns of molecular dynamics simulation at room temperature, during which no major changes occurred in the peptide. The molecule has been synthesised and purified. Two-dimensional NMR spectroscopy provided 35 distance and 7 torsion angle constraints, which were used to determine the three-dimensional structure. The experimental conformation agrees with the predicted one at the beta-turn, but deviates in the arrangement of the disulphide bridge that closes the backbone to a ring. A 1.2 ns simulation at 600 K provided extended sampling of conformation space. The disulphide bridge reoriented into the experimental arrangement, producing a minimum backbone rmsd from the experimental conformation of 0.8 A. At a later stage in the simulation, a transition at Ser3 produced more pronounced high-temperature behaviour. The peptide hydrolyses p-nitrophenyl acetate about nine times faster than free histidine.

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organization
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Contribution to journal
publication status
published
subject
keywords
Amino Acid Sequence, Computer Simulation, Hydrolysis, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Molecular Structure, Nitrophenols, Peptides, Cyclic, Protein Conformation, Serine Endopeptidases, Thermodynamics
in
Journal of Computer-Aided Molecular Design
volume
10
issue
1
pages
12 pages
publisher
Kluwer
external identifiers
  • Scopus:0030076901
ISSN
0920-654X
DOI
10.1007/BF00124461
language
English
LU publication?
yes
id
fb1f5fa7-fa6b-461f-a803-c3d6517341a9
date added to LUP
2016-04-18 16:02:46
date last changed
2017-01-01 08:23:15
@article{fb1f5fa7-fa6b-461f-a803-c3d6517341a9,
  abstract     = {<p>We report the design of a cyclic, eight-residue peptide that possesses the catalytic triad residues of the serine proteases. A manually built model has been relaxed by 0.3 ns of molecular dynamics simulation at room temperature, during which no major changes occurred in the peptide. The molecule has been synthesised and purified. Two-dimensional NMR spectroscopy provided 35 distance and 7 torsion angle constraints, which were used to determine the three-dimensional structure. The experimental conformation agrees with the predicted one at the beta-turn, but deviates in the arrangement of the disulphide bridge that closes the backbone to a ring. A 1.2 ns simulation at 600 K provided extended sampling of conformation space. The disulphide bridge reoriented into the experimental arrangement, producing a minimum backbone rmsd from the experimental conformation of 0.8 A. At a later stage in the simulation, a transition at Ser3 produced more pronounced high-temperature behaviour. The peptide hydrolyses p-nitrophenyl acetate about nine times faster than free histidine.</p>},
  author       = {Walse, B and Ullner, M and Lindbladh, C and Bülow, L and Drakenberg, T and Teleman, O},
  issn         = {0920-654X},
  keyword      = {Amino Acid Sequence,Computer Simulation,Hydrolysis,Magnetic Resonance Spectroscopy,Models, Molecular,Molecular Sequence Data,Molecular Structure,Nitrophenols,Peptides, Cyclic,Protein Conformation,Serine Endopeptidases,Thermodynamics},
  language     = {eng},
  number       = {1},
  pages        = {11--22},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy},
  url          = {http://dx.doi.org/10.1007/BF00124461},
  volume       = {10},
  year         = {1996},
}