IMI - Webmail

Combined molecular modelling and experimental studies of physiologically and stereochemically important copper(II) amino acid complexes – CopperAminoAcidates

PROJECT ACRONYM: CopperAminoAcidates

Funded by the Croatian Science Foundation under Project No. IP-2014-09-3500

1 Sep 2015-28 Jan 2021

Abstract

Bis(amino acidato)copper(II) complexes, Cu(aa)2, have been known since the second half of the 19th century but their intensive structural studies started in the 1960s and continue up to date. The studies have been motivated by (1) the finding that they are biologically important compounds as a part of the accessible physiological pool for transport and storage of the essential element copper, the fact that (2) they could be appropriate model compounds for copper-binding sites in metalloproteins, and the fact that (3) they are stereochemically interesting compounds. Bis(L-histidinato)copper(II), Cu(L-His)2, and the ternary bis-cooper(II) complexes with L-histidine and other L-amino acids (preferably L-glutamine, L-threonine, L-arginine, and some studies suggested L-cysteine) were determined as the predominant Cu(aa)2 in the blood. Stereochemically and stereoselectively, Cu(aa)2 are a very interesting class of compounds because of (1) various possible copper(II) coordination geometries, and (2) the ability of amino acids to bind to copper(II) either in a trans– or a cis-configuration. Trans and cis isomers for many Cu(aa)2 were identified to simultaneously exist in aqueous solutions by 14N superhyperfine structure in electron paramagnetic resonance spectra. The 13C and 2H fast magic-angle spinning solid-state NMR (ssNMR) spectra suggested that the isopropyl groups were static in trans-bis(L-valinato)copper(II) but could jump between different positions and adopt different conformations in the cis isomer, even at room temperature (Szalontai et al., Eur J Inorg Chem 2014: 3330). However, the cis-trans interconversion could occur in different solvent composition ratios, and the cis-trans isomerisation requires additional studies to be completely understood. Despite the extensive experimental physico-chemical characterisation studies of Cu(aa)2 in aqueous solutions attempted during the past 40 years, most studies gave information only on the first copper(II) coordination sphere (i.e., the number of nitrogen atoms attached to the copper(II) and their cis or trans position), and their exact structures in solution generally remain unresolved. On the contrary, complete structural information can be obtained by molecular modelling methods, such as quantum chemistry density functional theory (DFT), molecular mechanics (MM), and molecular dynamics (MD). Our recent DFT study of Cu(L-His)2 (Marković et al., Eur J Inorg Chem 2014: 198) is the first that clarified the structure of that physiologically important compound in aqueous solution at physiological conditions. Our computational results, obtained using the environment-free MM force field FFWa-SPCE (Sabolović et al., J Chem Theory Comput 2009, 5: 1940) for modelling of copper(II) complexes with aliphatic amino acids in vacuum, aqueous solution and solid state (by using the same set of potential energy functions and empirical parameters), were essential to understand the experimental results about the processes occurring at the molecular level in solution and influenced the isomerisation and crystallisation of specific isomers and/or conformers. The main goal of the project is to obtain new results on the physico-chemical properties (structure, energy, vibrations, cis–trans isomerism, conformational changes) in different surroundings (vacuum, aqueous solution, solid state) of the physiological Cu(aa)2 and selected copper(II) complexes with aliphatic amino acids because of their biological importance and stereochemical diversity by using the molecular modelling (DFT, MM, MD) and experimental (X-ray diffraction techniques, ssNMR) methods. We plan to develop a new environment-free MM force field for the physiological Cu(aa)2 by using the new DFT results and already published crystal structures as data set for the force field development. By combining these methods we expect to contribute to solving yet unresolved issues of the exact geometries in solution and solid state and of the processes occurring at molecular level. The new results will contribute to understanding the data required in the discovery of new potential drugs, since the detailed physico-chemical characterisation is a necessary first step in the drug development. It is worth mentioning that the interest in copper coordination complex research as antiproliferative agents has markedly increased in the last few years. We expect our results to have an impact on applications in bioinorganic chemistry, biophysics, biology, and medicine.

PRINCIPAL INVESTIGATOR

Jasmina Sabolović, PhD; Institute for Medical Research and Occupational Health (IMROH)
(jasmina.sabolovic@imi.hr)

TEAM MEMBERS

Jelena Pejić (Budimčić); Institute for Medical Research and Occupational Health (IMROH)
(jbudimcic@imi.hr)
Marijana Marković (marijana.markovic@zg.t-com.hr) (until 1 Nov 2017)
Draginja Mrvoš-Sermek, University of Zagreb, Facutly of Science, Zagreb, Croatia
(mrvos@chem.pmf.hr) (until 12 Sep 2018)
Gábor Szalontai, University of Pannonia, Veszprém, Hungary
(Szalontai.Gabor@solidnmr.hu)
Michael Ramek, Graz University of Technology, Graz, Austria
(michael.ramek@tugraz.at)
Darko Vušak, University of Zagreb, Faculty of Science (dvusak@chem.pmf.hr) (from 24 Sep 2018)

LIST OF PUBLICATIONS

SCIENTIFIC PAPERS

  1. Ramek, Michael; Pejić, Jelena; Sabolović, Jasmina: STRUCTURE PREDICTION OF NEUTRAL PHYSIOLOGICAL COPPER(II) COMPOUNDS WITH L-CYSTEINE AND L-HISTIDINE, J. Inorg. Biochem. 2021, 223, 111536 (1-16). https://www.sciencedirect.com/science/article/pii/S0162013421001835?via%3Dihub [IF (2020) = 4.155, 9/45 (CHEMISTRY, INORGANIC & NUCLEAR) Q1]
  2. Pejić, Jelena; Ramek, Michael; Sabolović, Jasmina: MOLECULAR MODELLING STUDY OF PHYSIOLOGICAL COPPER(II) COMPOUNDS WITH L-GLUTAMINE AND L-HISTIDINE, u izradi
  3. Marković, Marijana; Ramek, Michael; Loher, Claudia; Sabolović, Jasmina: THE IMPORTANT ROLE OF THE HYDROXYL GROUP ON THE CONFORMATIONAL ADAPTABILITY IN BIS(L-THREONINATO)COPPER(II) COMPARED TO BIS(L-ALLO-THREONINATO)COPPER(II): QUANTUM CHEMICAL STUDY, Inorg. Chem. 2016, 55(15), 7694-7708. [IF (2015) = 4.820, Q1] https://pubs.acs.org/doi/abs/10.1021/acs.inorgchem.6b01157
  4. Ramek, Michael; Marković, Marijana; Loher, Claudia; Sabolović, Jasmina: PRONOUNCED CONFORMATIONAL FLEXIBILITY OF PHYSIOLOGICAL (L-HISTIDINATO)(L-THREONINATO)COPPER(II) IN AQUEOUS SOLUTION DISCLOSED BY A QUANTUM CHEMICAL STUDY, Polyhedron 2017, 135, 121-133. (http://authors.elsevier.com/a/1VQi8_6JtpgcSR; http://www.sciencedirect.com/science/article/pii/S027753871730459X) [IF (2016) = 1.926, Q2]
  5. Sabolović, Jasmina; Ramek, Michael; Marković, Marijana: CALCULATING THE GEOMETRY AND RAMAN SPECTRUM OF PHYSIOLOGICAL BIS(L-HISTIDINATO)COPPER(II): AN ASSESSMENT OF DFT FUNCTIONALS FOR AQUEOUS AND ISOLATED SYSTEMS, J. Mol. Model. 2017, 23, 290. http://doi.org/10.1007/s00894-017-3448-z [IF (2016) = 1.425, Q3] http://em.rdcu.be
  6. Pejić, Jelena; Vušak, Darko; Szalontai, Gábor; Prugovečki, Biserka; Mrvoš-Sermek, Draginja; Matković-Čalogović, Dubravka; Sabolović, Jasmina: DISORDER AT THE CHIRAL CΑ CENTER AND ROOM-TEMPERATURE SOLID-STATE CIS–TRANS ISOMERIZATION; SYNTHESIS AND STRUCTURAL CHARACTERIZATION OF COPPER(II) COMPLEXES WITH d-ALLO,l-ISOLEUCINE. Cryst. Growth Des. 2018, 18, 5138-5154. https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00589 [IF (2017) = 3.972, Q1]
  7. Ramek, Michael; Marković, Marijana; Mutapčić, Ilina; Pejić, Jelena; Kelterer, Anne-Marie; Sabolović, Jasmina: CONFORMATIONAL ANALYSES OF PHYSIOLOGICAL BINARY AND TERNARY COPPER(II) COMPLEXES WITH l-ASPARAGINE AND l-HISTIDINE; STUDY OF TRIDENTATE BINDING OF COPPER(II) IN AQUEOUS SOLUTION. Chemistry Open, 2019, 8, 852-868. https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/open.201900159 (open access) [IF (2018) = 2.37, 90/177 (Chemistry, Multidisciplinary) Q3]
  8. Vušak, Darko; Pejić, Jelena; Jurković, Mia; Szalontai, Gábor; Sabolović, Jasmina: COORDINATION POLYMERS OF PARAMAGNETIC BIS(LEUCINATO)COPPER(II) DIASTEREOMERS: EXPERIMENTAL AND COMPUTATIONAL STUDY OF THE STEREOISOMERISM AND CONFORMATIONS. Cryst Eng Comm, 2020, 22; 5587-5600. https://pubs.rsc.org/en/content/articlehtml/2020/ce/d0ce00585a [IF (2020) = 3.545, 6/26 (Crystallography) Q1].

  1. Ramek, Michael; Pejić, Jelena; Sabolović, Jasmina: STRUCTURE PREDICTION OF NEUTRAL PHYSIOLOGICAL COPPER(II) COMPOUNDS WITH L-CYSTEINE AND L-HISTIDINE, 2021, submitted
  2. Pejić, Jelena; Ramek, Michael; Sabolović, Jasmina: MOLECULAR MODELLING STUDY OF PHYSIOLOGICAL COPPER(II) COMPOUNDS WITH L-GLUTAMINE AND L-HISTIDINE, in preparation

ABSTRACTS IN CONFERENCE BOOKS

Invited lectures:

  1. Marković, Marijana; Ramek, Michael; Sabolović, Jasmina: A DENSITY FUNCTIONAL THEORY STUDY OF THE COORDINATION MODES OF PHYSIOLOGICAL BIS(L-HISTIDINATO)COPPER(II): THE IMPORTANCE OF INTERMOLECULAR INTERACTIONS, 1st International Caparica Christmas Conference on Translational Chemistry IC3TC 2015, Caparica – Almada (Lisabon), Portugal, 7-10 December 2016, Book of Abstracts, p 60 (O 6A)-60 (ISBN: 978-989-99361-7-1).

Oral presentations:

  1. Marković, Marijana; Ramek, Michael; Loher, Claudia; Sabolović, Jasmina. WEAK INTRAMOLECULAR INTERACTIONS IN BIS(L-THREONINATO)COPPER(II) COMPARED TO BIS(L-ALLO-THREONINATO)COPPER(II). 3rd Symposium on Weak Molecular Interactions, Opole, Poland, 27-29 March 2017, Bookof Abstracts, pp 46-47.
  2. Budimčić, Jelena; Ramek, Micheal; Sabolović, Jasmina: MECHANISMS OF CIS–TRANS ISOMERIZATION AND CΑ EPIMERIZATION OF (d-ALLO,l-ISOLEUCINATO)COPPER(II). 58th Sanibel Symposium, St. Simons Island, Sjedinjene Američke Države, 18-23 Feb 2018, Final Program
  3. Szalontai, Gábor; Sabolović Jasmina: ssNMR SPECTROSCOPY, CRYSTALLOGRAPHY AND COMPUTATION OF PARAMAGNETIC BIS AMINO ACID (ĸ2N,O) COPPER(II) COMPLEXES. A JOINT APPROACH. SMARTER6, Ljubljana, Slovenija, 2-6 Sep 2018. Book of Abstracts, pg. 26.

Posters:

  1. Marković, Marijana; Ramek, Michael; Loher, Claudia; Sabolović, Jasmina: QUANTUM CHEMICAL STUDY OF BIS(L-THREONINATO)COPPER(II) IN THE GAS PHASE AND AQUEOUS SOLUTION, ISTERH 2015 „Recent Advances in Trace Element Research in Health and Disease“ Srebreno, Hrvatska, 18-22 October 2015, J. Trace Elem. Med. Biol., Abstracts XI. ISTERH Conference, 2015, 32S1, 24. [IF (2015) = 2.550, Q3]
  2. Budimčić, Jelena; Sabolović, Jasmina. CONFORMATIONAL ANALYSIS OF THE BIS(D,L-ISOLEUCINATO)COPPER(II) COMPLEX IN AQUEOUS SOLUTION, 25th Croatian Meeting of Chemists and Chemical Engineers with international participation, Poreč, Croatia, 19 – 22 April 2017, Knjiga sažetaka / Book of abstracts, pp 113.
  3. Ramek, Michael; Marković, Marijana; Loher, Claudia; Sabolović, Jasmina. QUANTUM CHEMICAL CONFORMATIONAL ANALYSES UNVEIL CONFORMATIONAL FLEXIBILITY OF PHYSIOLOGICAL (L-HISTIDINATO)(L-THREONINATO)COPPER(II) IN AQUEOUS SOLUTION, 11th Triennale Congfress of the World Association of Theoretical and Computational Chemists – WATOC 2017, Munich, Germany, 27 August – 1 September 2017, Book of Abstracts with Scientific Program, PO2-34.
  4. Marković, Marijana; Ramek, Michael; Mutapčić, Ilina; Sabolović, Jasmina. CONFORMATIONAL ANALYSES OF BIS(L-ASPARAGINATO)COPPER(II) IN THE GAS PHASE AND IN AQUEOUS SOLUTION. 11th Triennale Congfress of the World Association of Theoretical and Computational Chemists – WATOC 2017, Munich, Germany, 27 August – 1 September 2017, Book of Abstracts with Scientific Program, PO2-145.
  5. Budimčić, Jelena, Ramek, Marković, Marijan; Mutapčić, Ilina; Sabolović, Jasmina: QUANTUM CHEMICAL STUDY OF (L-HISTIDINATO)(L-ASPARAGINATO)COPPER(II) IN THE GAS PHASE AND AQUEOUS SOLUTION. 17. ÖSTERREICHISCHE CHEMIETAGE 17th Austrian Chemistry Days Joint Meeting of the Swiss & Austrian Chemical Societies; Salzburg, Austija 25-28. Sep 2017. Book of Abstracts pg. PO-153.
  6. Pejić, Jelena; Sabolović, Jasmina: CONFORMATIONAL ANALYSIS OF (D-ALLO-ISOLEUCINATO)(L-ISOLEUCINATO)COPPER(II) IN AQUEOUS SOLUTION BY MOLECULAR DYNAMICS SIMULATION, BioExcel Summer School on Biomolecular Simulations, Pula (Sardinija), Italija, 30. lipnja – 5. srpnja 2019. (unpublished)
  7. Sabolović, Jasmina; Kelterer, Anne-Marie; Ramek, Michael: DFT-CALCULATED MAGNETIC PARAMETERS OF PHYSIOLOGICAL COPPER(II) COMPLEXES WITH L-ASPARAGINE AND L-HISTIDINE: A TOOL FOR VERIFICATION OF PREDICTED LOWER-ENERGY CONFORMERS IN AQUEOUS SOLUTION, ISTCP 2019 10th Triennial Congress of the International Society for Theoretical Chemical Physics, Tromsø, Norveška, 11-17. srpnja 2019.; ISTCP-X Book of abstracts, P1-95

PUBLIC LECTURES

  1. Szalontai, Gábor: STRUCTURE DETERMINATION OF STEREOISOMERS IN PARTIALLY ORIENTED AND SOLID PHASES BY 2H NMR, 16 June 2016, organizer: IMROH
  2. Sabolović, Jasmina: COMBINED MOLECULAR MODELLING AND EXPERIMENTAL STUDIES OF PHYSIOLOGICALLY AND STEREOCHEMICALLY IMPORTANT COPPER(II) AMINO ACID COMPLEXES, 8 July 2019, organizer: IMROH