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

Björn Walse, Magnus Ullner, Christer Lindbladh, Leif Bulow, Torbjörn Drakenberg, Olle Teleman

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)

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 β-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 Å. 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.
Original languageEnglish
Pages (from-to)11-22
Number of pages12
JournalJournal of Computer-Aided Molecular Design
Volume10
Issue number1
DOIs
Publication statusPublished - 1996
MoE publication typeA1 Journal article-refereed

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Cyclic Peptides
Computer Simulation
Peptides
Nuclear magnetic resonance spectroscopy
peptides
Conformations
Magnetic Resonance Spectroscopy
computerized simulation
disulfides
Disulfides
nuclear magnetic resonance
Computer simulation
spectroscopy
protease
Temperature
simulation
histidine
Serine Proteases
Molecular Dynamics Simulation
Histidine

Cite this

Walse, Björn ; Ullner, Magnus ; Lindbladh, Christer ; Bulow, Leif ; Drakenberg, Torbjörn ; Teleman, Olle. / Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy. In: Journal of Computer-Aided Molecular Design. 1996 ; Vol. 10, No. 1. pp. 11-22.
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title = "Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy",
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 β-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 {\AA}. 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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Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy. / Walse, Björn; Ullner, Magnus; Lindbladh, Christer; Bulow, Leif; Drakenberg, Torbjörn; Teleman, Olle.

In: Journal of Computer-Aided Molecular Design, Vol. 10, No. 1, 1996, p. 11-22.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Structure of a cyclic peptide with a catalytic triad, determined by computer simulation and NMR spectroscopy

AU - Walse, Björn

AU - Ullner, Magnus

AU - Lindbladh, Christer

AU - Bulow, Leif

AU - Drakenberg, Torbjörn

AU - Teleman, Olle

PY - 1996

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N2 - 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 β-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 Å. 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.

AB - 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 β-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 Å. 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.

U2 - 10.1007/BF00124461

DO - 10.1007/BF00124461

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SN - 0920-654X

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