Copper(II)-binding ability of stereoisomeric cis- and trans -2-aminocyclohexanecarboxylic acid-l-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study

N. Nagy, Sabine Van Doorslaer, T. Szabó-Plánka, Senne Van Rompaey, A. Hamza, F. Fülöp, G. Tóth, A. Rockenbauer

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Abstract

With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of l-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)] 2+, [CuL] +, [CuLH -1], [CuLH -2] -, and [CuL 2H -1] -), and an EPR-inactive species ([Cu 2L 2H -3] -) in aqueous solutions for all studied cases. [CuLH] 2+ was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL 2], together with two coordination isomers of [CuL 2H -1] -, were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH -1] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band 1H HYSCORE, 2H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH -1] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.

Original languageEnglish
Pages (from-to)1386-1399
Number of pages14
JournalInorganic Chemistry
Volume51
Issue number3
DOIs
Publication statusPublished - Feb 6 2012

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phenylalanine
Dipeptides
Phenylalanine
Discrete Fourier transforms
Paramagnetic resonance
Copper
Isomers
copper
acids
isomers
Complexation
peptides
Design for testability
Ligands
Peptides
ligands
Stereoisomerism
rings
destabilization
superhigh frequencies

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Physical and Theoretical Chemistry

Cite this

@article{9a68cbe12bc34c03921b76d3e4d83fbd,
title = "Copper(II)-binding ability of stereoisomeric cis- and trans -2-aminocyclohexanecarboxylic acid-l-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study",
abstract = "With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of l-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)] 2+, [CuL] +, [CuLH -1], [CuLH -2] -, and [CuL 2H -1] -), and an EPR-inactive species ([Cu 2L 2H -3] -) in aqueous solutions for all studied cases. [CuLH] 2+ was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL 2], together with two coordination isomers of [CuL 2H -1] -, were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH -1] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band 1H HYSCORE, 2H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH -1] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.",
author = "N. Nagy and Doorslaer, {Sabine Van} and T. Szab{\'o}-Pl{\'a}nka and Rompaey, {Senne Van} and A. Hamza and F. F{\"u}l{\"o}p and G. T{\'o}th and A. Rockenbauer",
year = "2012",
month = "2",
day = "6",
doi = "10.1021/ic2016116",
language = "English",
volume = "51",
pages = "1386--1399",
journal = "Inorganic Chemistry",
issn = "0020-1669",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Copper(II)-binding ability of stereoisomeric cis- and trans -2-aminocyclohexanecarboxylic acid-l-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study

AU - Nagy, N.

AU - Doorslaer, Sabine Van

AU - Szabó-Plánka, T.

AU - Rompaey, Senne Van

AU - Hamza, A.

AU - Fülöp, F.

AU - Tóth, G.

AU - Rockenbauer, A.

PY - 2012/2/6

Y1 - 2012/2/6

N2 - With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of l-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)] 2+, [CuL] +, [CuLH -1], [CuLH -2] -, and [CuL 2H -1] -), and an EPR-inactive species ([Cu 2L 2H -3] -) in aqueous solutions for all studied cases. [CuLH] 2+ was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL 2], together with two coordination isomers of [CuL 2H -1] -, were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH -1] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band 1H HYSCORE, 2H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH -1] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.

AB - With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of l-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)] 2+, [CuL] +, [CuLH -1], [CuLH -2] -, and [CuL 2H -1] -), and an EPR-inactive species ([Cu 2L 2H -3] -) in aqueous solutions for all studied cases. [CuLH] 2+ was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL 2], together with two coordination isomers of [CuL 2H -1] -, were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH -1] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band 1H HYSCORE, 2H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH -1] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.

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U2 - 10.1021/ic2016116

DO - 10.1021/ic2016116

M3 - Article

VL - 51

SP - 1386

EP - 1399

JO - Inorganic Chemistry

JF - Inorganic Chemistry

SN - 0020-1669

IS - 3

ER -