The binding abilities of homodetic cyclic His-peptides toward copper ions

Accepted Manuscript The binding abilities of homodetic cyclic His-peptides toward copper ions Aleksandra Kotynia, József Sándor Pap, Justyna Brasun PII: DOI: Reference:

S0020-1693(17)30672-2 http://dx.doi.org/10.1016/j.ica.2017.07.028 ICA 17751

To appear in:

Inorganica Chimica Acta

Received Date: Revised Date: Accepted Date:

9 May 2017 4 July 2017 12 July 2017

Please cite this article as: A. Kotynia, J.S. Pap, J. Brasun, The binding abilities of homodetic cyclic His-peptides toward copper ions, Inorganica Chimica Acta (2017), doi: http://dx.doi.org/10.1016/j.ica.2017.07.028

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The binding abilities of homodetic cyclic His-peptides toward copper ions Aleksandra Kotyniaa, József Sándor Papb, Justyna Brasuna*

a

Department of Inorganic Chemistry, Wroclaw Medical University, Borowska 211A, 50-552

Wrocław, Poland, * [email protected] b

Surface Chemistry and Catalysis Department, Centre for Energy Research, Hungarian

Academy of Sciences, 1525 Budapest 114, P.O. Box 49, Budapest, Hungary

"Cylic peptides represent an appealing platform for Cu 2+binding and reaching refined applications"

Abstract The biochemistry of copper is important and worthy to be broadly studied. In biological systems copper is usually bound by enzymes, proteins or peptides and the investigation of the occurring interactions is still a hot topic. In this overview we focus on the copper binding abilities of homodetic cyclic peptides (CPs) containing histidine moieties. This group of ligands is characterized by a cyclic ring composed only of amino acids. Several applications of cyclic peptides should be viable because of their special structures, stability and resistance against enzymatic degradation. The cyclic structure promotes the anchoring of metal ions by 1

the amino acid side chains. We discuss the impact of peptide cyclization and ring size on the binding abilities toward copper(II) ions. We also compare the coordinating properties of ligands containing a different number of His residues with the –(HX)n- motif , where X = Gly, Lys, Arg, Asn or Pro, based on the stability constants of nNIm (n=2-4) complexes created by His4-cyclopeptides. In addition, we compare the sustainability and stability of nNIm (n=1-4) complexes depending on the Asp residue in the peptide sequence and we also consider the aspects of forming dinucelar copper(II) complexes by cyclopeptides with two separated Pro residues in the sequence. The di-Cu(II)-complexes are favored in the basic pH range. So far, cyclopeptides found use in pharmaceutical chemistry, biochemistry, and life sciences, but also as ionophores and nano-materials. We advocate here to use their metal ion complexes because they enrich the spectrum of available activities of metallopeptides or change the properties of these ligands.

Keywords copper; complex; cyclic peptide; histidine; stability constant

Introduction Copper plays a significant role in biological systems. Several metalloproteins and active centers of metalloenzymes show a copper-specific activity that is regulated through the binding affinity and the coordination sphere. Moreover, the transport and storage of this metal in living systems depend on peptide/protein-metal complex stabilities [1-4]. Dysregulations of copper homeostasis may be linked to serious diseases such as Wilson's disease or some neurodegenerative disorders [5-11]. Numerous studies have been performed on linear fragments of peptides that are important from a biological or medical point of view in order to explore copper homeostasis

2

and its impact on pathological processes including interactions with β-amyloid [12-16], prion protein fragments [17, 18] or glutathione [19, 20]. Furthermore, linear and branched peptides are good chemical models that can be applied for catalytic purposes [21, 22] or mimicking various biological reactions, e.g., superoxide dismutase-like (SOD-like) activity [23-26]. Coordination geometries that are unavailable with linear peptide-metal complexes may be achieved by peptide branching [27, 28] or by designing particular oligopeptides that mimic the metal binding properties of the active centers of small metalloproteins [29-33]. The peptide cyclization strategy allows to investigate the impact of amino acid side chain donor groups on cyclic peptide frames, which, in relation to linear analogues are less flexible and stabilize certain metal-binding environments. Natural cyclic peptides (CPs) are often cyclized by a disulfide bridge, e.g., the hormones somatostatin, oxytocin, and vasopressin [34, 35], or formed by a peptide bond such as in bacitracin [36]. This leads to the study of models of various substances as therapeutics, ionophores, hormones, toxins, and antibiotics [37-40]. Such a spectrum of activities may be expanded by other methods for cyclization [41, 42] including cyclization templated by metal binding [43-45]. Note that strategies for the synthesis of CPs have been reviewed by others recently, therefore these will be not discussed here [41, 42]. Primarily, cyclization causes significant stiffening of the structure [46], influences the steric arrangement of the side chains [47], and allows to mimic the secondary structure of some protein fragments [48-50]. It has also been shown that CPs are more stable under physiological conditions than linear analogues and, in some cases, exhibit higher affinity for receptor binding [46, 47]. It was also shown that cyclic peptides exhibit specificity in the binding of certain metal ions. Studies with cyclopeptides like vasopressin or oxytocin have shown that these apparently naturally metal-free substances effectively bind metal ions [51, 52]. Based on their 3

unique structural abilities, CPs have been used as biomimetics to study the biological activity of human collagenase VI and its specificity in Ca2+-binding [53], the abilities of metalloproteinases (MMPs) [54], and as model systems for Ca2+-binding by the α-lactalbumin loop [55]. Moreover, cyclic peptides with certain arrangements of side chains have been investigated as chemosensors for metal ions [56] or chelators for Ln3+ ions [57]. To summarize, the large number of applications and the huge potential for the functionalization of cyclic peptide scaffolds make CPs interesting models for studying biologically relevant interactions with metals as well as ligands for a wide range of applications, especially when functionalized with metal binding residues like in histidine (His), aspartic acid (Asp) and/or proline (Pro). The present review focuses on homodetic, cyclic His-containing peptides and the characterization of interactions between these compounds and copper(II) ions by providing examples from the current literature.

The influence of cyclization on the binding abilities The mentioned homodetic, cyclic Hisn-peptides have been obtained by peptide bond formation between the N-terminal amine and the C-terminal carboxylate groups of linear precursors. The impact of the N-terminal amino group (also known as the metal ion anchoring group) on complex formation is observed also in His-containing peptides [58-62], despite the particular affinity of His toward Cu(II). Obviously, as these termini do not exist in CPs, the sequence of amino acids will be the crucial factor in the metal binding abilities. For the above reasons the elucidation of the effect of cyclisation on the metal binding abilities of the peptides should be done by considering linear compounds with a protected N-terminal amino group as reference (Table 1).

4

Table 1. Comparison of stability constants (logβ*n×Im) and pK values related to the histidine imidazole and amide group deprotonation (first, second and third) of selected complexes formed by cyclic peptides and their linear analogues.

Ligand

1×NIm

c(HG) [63] Ac-HGGG [64] c(HGHK) [65] Ac-HGHG [66] c(HGHRHG) [67] Ac-HGHVH-NH2 [68] c(GNWHPGHKHP) [69] Ac-GNWHPGHKHG-NH2 [69] c(HGHGHGHG) [70]

3.35 4.20 3.98 4.10 4.42 -

c(HGHKHGHK) [71] c(HKHPHKHP) [72] c(HKHGPGHKHGPG) [73]

-

Logβ* n×Im 2×NIm 3×NIm 4×NIm 6.17 6.49 5.63 6.17 6.03 5.92 5.30 4.84 5.75

7.47 8.07 9.11 8.17 7.34 -

N1

-

-

9.35 9.42 8.46 9.81

pK N2 -

N3 -

a)

6.60 5.75 6.09 5.44 6.83 7.63 7.25

6.96 6.73 6.53 6.59 7.27 8.02 7.34

8.92 10.28 10.44 8.67 9.03

a)

-

pK1 + pK2 14.28 10.37 14.82 8.72 15.25 9.23

a) data not available logβ* = logβCuHxL - logβHyL

The available data shown in Table 1 suggest that in Cu(II)-complexes the interactions with the imidazole nitrogen of His residues of c(HX)n, where n = 1-3 and X = non-Cu-binding side chain amino acid (Scheme 1), are less pronounced compared to linear analogues. Moreover, the pK of the peptide amide nitrogens, in most cases, indicate that cyclic structures generally promote the involvement of those donors, as it was observed for analogues of oxytocin or vasopressin with a free N-terminal group [51, 74].

5

Scheme 1. Schematic structures of the cyclic Hisn-peptides, where n=1, 2, 3 or 4 respectively.

The comparison of the abilities of Cu(II) binding between the cyclic tetrapeptide c(HGHK) and Ac-HGHG [66] is presented in Fig. 1a. Both ligands form the same type of complexes: metal binding starts by involving only imidazole donors and above pH 6 the coordination of amide donors takes place. Despite the fact that both peptides form the same type of complexes, they differ in the efficiency of Cu(II) binding (Fig. 1b). Below pH 6 (where the involvement of imidazole coordination dominates), the cyclic peptide is a more effective ligand. However, both peptides bind Cu(II) with similar affinities when additional amide donors are involved, at pH higher than 6.5. (a) -

{2NIm, 2N l} 100

% formation relative to Cu(II)

-

{2NIm, N } 80

-

{3N , NIm }

{2NIm} 60

40

20

{NIm}

0 4

6

8

10

pH

(b)

6

% formation relative to Cu(II)

100

80

c(HGHK) Cu(II)

60

40

Ac-HGHG

20

0 4

6

8

10

pH

Figure 1. Plots comparing the Cu(II) binding effectivity between c(HGHK) – solid lines [65] and Ac-HGHG – dashed lines [66] as a function of pH: (a) competition diagram, (b) species distribution. The situation changes for ligands of the c(HX)3 type (Fig. 2a) where a higher efficacy in metal binding by amide groups is observed for cyclic structures. In the case of a larger peptide couple, c(GNWHPGHKHP)/Ac-GNWHPGHKHG-NH2 that contains additional sequential non-His motives the cyclic ligand is more effective in Cu(II) coordination within the entire pH range (Fig. 2b).

(a)

% formation relative Cu(II)

100

80

Cu(II) c(GHRHGH)

60

40

Ac-HGHVH-NH2 20

0 4

6

8

10

pH

7

(b)

% formation relative to Cu(II)

100

80

Cu(II) c(GNWHPGHKP)

60

40

20

Ac-GNWHPGHKG-NH2

0 4

6

pH

8

10

Figure 2. Competition plots presenting the Cu(II) binding effectivity between cyclic peptides (solid line) and their linear analogues (dashed line) as a function of pH: (a) c(HGHRHG) [67]/Ac-HGHVH-NH2 [68], (b) c(GNWHPGHKHP)/Ac-GNWHPGHKHG-NH2 [69]. The coordination abilities of cyclic peptides with the –(HX)n- motif Various combinations and numbers of -HX- motive repeats, where X = Gly, Lys, Arg, Asn or Pro, in cyclic peptides resulted in a series of ligands that offer adjustable affinity to bind Cu(II) ions. The cyclic α-peptide with a c(HG) sequence was the first one of the investigated ligands (Scheme 1). Potentiometric and thermodynamic studies by Arena and co-workers indicated that this ligand, in the presence of Cu(II) ions forms two types of complexes: CuL and CuL2 dominating between pH 3.1 and 6.0. Deprotonation of the amide group could not be observed [63]. The stability constant of the species with one imidazole donor, logβ* = 3.35 was the lowest compared to the entire group of cyclic multiples that have been investigated (Table 1). Based on the available data it can be stated that in the case of c(HX)n (n=1,2,3) peptides, if the {1×NIm} coordination mode is considered, the stability grows with the value of n= 1<2<3. Simultaneously, the complex formed with the {2×NIm} donor set is getting more stable with increasing n (n= 2<3<4) (Table 1).

8

The analysis of the speciation of complexes over a broad range of pH values for several metal ligand systems showing different copper(II) coordination patterns is presented in Table 2. Data are provided for three types of cyclic peptides, c((HX)n) n = 2, 3, 4 (Scheme 1) [65, 67, 69, 71, 73, 75].

Scheme 2. Schematic structures of selected cyclic His4-peptides.

The c(HGHK) as well as the c(HGHRHG) ligand form the same complexes dominating in the same range of pH (Table 2). The presence of an additional -HX- motif in the cycle stabilizes a complex species with four imidazole donors in the coordination sphere of the metal ion. The other difference between the two former ligands and c(HGHKHGHK) is the ability of the latter to bind the metal by a third amide donor.

Table 2. Schematic presentation of the Cu(II) coordination environment in the complexes with c(-(HisXaa)n), where n = 1-4 and X = Gly, Pro, Lys or Arg [65, 67, 69, 7173]. The conditions refer to CCu(II) = 0.001M and 1:1 metal-ligand molar ratio. Color code: the involvement of only imidazole nitrogens – yellow, first amide nitrogen – blue, second amide nitrogen – red, third amide nitrogen – green.

9

Modification of the (-(HX)3)-like sequence by additional, non-His amino acid residues like in the case of the cyclic decapeptide c(GNWHPGHKHP) results in different stabilities of the complexes which puts emphasis on the role of the flexibility concerning the overall peptide ring in the interactions of the c(HX)n domains with metal ions. Although the three imidazole containing decapeptide complex is significantly more stable than the hexapeptide analogue of a smaller ring size (logβ* c(GNWHPGHKHP) = 9.11 [69] vs. logβ* c(HGHRHG) = 7.47 [67], where logβ*= logβCuHL- logβHL); it is the cyclic hexapeptide that promotes coordination of the amide donors (Table 1). Cycles with four -HX- motifs bind Cu(II) ions by a {4×Nim} donor set up to pH 7 [71, 73, 75]. At higher pH, copper ions are bound by the {2×NIm, 2×N−am} donor set, similarly to peptides with two or three -(HX)2- moieties like c(HGHK) and c(HGHRHG), respectively. In the more alkaline pH range of 9 to10.5 the coordination of an additional amide nitrogen donor takes place (Table 2). The occurrence as well as the stability of the species with the {4×NIm} coordination mode strongly depends on the possibility to form structural isomers with the peptide ring. The replacement of two Pro moieties in the c(HPHKHPHK) by Gly and obtaining the c(HGHKHGHK) sequence increases the peptide chain flexibility as well as the insertion of four additional Gly moieties (c(HGPGHKHGPGHK)) (Scheme 2). The logβ* of the {4×NIm} complexes,

were

logβ*=logβCuHxL-logβHxL,,

follow

the

order

c(HPHKHPHK)

<

c(HGHKHGHK) = c(HGHGHGHK) < c(HGPGHKHGPGHK) (Figure 2a). Moreover, the 10

binding efficiency also increases with increasing peptide ring flexibility near the physiological pH range (Fig. 3b). (a)

(b)

Figure 3. (a) Comparison of stability constants for Cu(II) complexes with the {n×Im} donors formed by His4-CPs. (b) Comparison of the efficacy of copper(II) binding in dependence on pH between: c(HKHPHKHP) (nL1 ), c(HKHGHKHG) (nL2), and c(HKHGPG HKHGPG) (nL3), where the molar ratio nM :nL1:nL2:nL3 is 1:1:1:1 and the Cu(II) concentration is 0.001 M.

The interactions of simple c(HX)4 cyclic tetrapeptides with two His residues toward Cu(II) may strongly depend also on the ring size. Scheme 3 shows the structure of three cyclic tetrapeptides characterized by a different ring size [76-78]. The first one consists only of α11

amino acid residues and forms a 12-membered ring (Scheme 3a). Due to the replacement of a Gly residue by βAla an additional -CH2- appears in the cycle and a 13-membered ring is formed (Scheme 3b). Finally, if Lys is replaced by its β-analogue, β3homoLys, the extension of the cycle with a further -CH2- yields a 14-membered ring (Scheme 3c).

Scheme 3. Structures of (a) 12-membered ring - c(HGDHK) and two modified tetrapeptides with: (b) 13-membered ring - c(DHβAHK), (c) 14-membered ring –c(HβADHβ3homoK). The first one, c(HGDHK) with a 12-membered ring, due to its relatively small ring size, binds Cu(II) by a {NIm,2×N-am} set at higher pH. Data for c(KDHβAH) indicate that extension of the ring size significantly changes the metal coordination pattern at higher pH and the {4N−am} binding mode is dominant with simultaneous oxidation of Cu(II) to Cu(III) in the solution by atmospheric O2 [78], however this process strongly depends on the presence and optical isomerism of His moieties [77]. Further expansion of the ring size by replacement of K with β3homoK results in the binding of Cu(II) by four amide donors arranged in square planar geometry at higher pH [76]. In case when a LHis is exchanged to its DHis isomer in the cyclic c(HX)2 tetrapeptide, at the physiological range of pH, only one imidazole nitrogen is involved in Cu binding in contrast to the LHis isomer [79]. Due to this modification, the LHis'LHis-CP is more effective in Cu(II) binding below pH 6 and above this pH the LHis DHis analogue is getting to be more effective because the involvement of the amide nitrogen donors is more favored. 12

It was also demonstrated that the Cu(II) binding affinity by c(HX)2 and the involvement of different donors as a function of pH may be also modified by the insertion of an aspartic acid residue (Asp). The peptide c(HGHD) forms an appreciably more stable complex with both imidazole nitrogen donor atoms bound to Cu(II) at the physiological pH range as a result of the additional involvement of the side chain -COO− group of Asp in metal coordination (Fig. 4a). It also causes the coordination of a second amide nitrogen at higher pH [79]. The impact of the Asp residue is also traced in a major increase in complex stability especially at physiological pH (Fig. 4a) [71, 79, 80]. Moreover, due to the additional presence of the –COO- side chain of the Asp residue in the coordination sphere of the metal ion the stability constants of complexes with imidazole donors are higher than with non-Asp ligands. (Fig. 4b). (a) 100

% formation relative Cu(II)

Cu(II) c(HGHD)

80

60

40

20

c(HGHK)

0 4

6

8

10

pH

13

(b)

Figure 4. (a) Competition plots showing the distribution of Cu(II) between c(HGHDHGHD)/c(HGHKHGHK) [71], (b) comparison of stability constants of n×NIm complexes.

The formation of dinuclear complexes Proline is the amino acid residue with a cyclic structure. The presence of Pro in the peptide chain influences the peptide structure, e.g., it promotes bending of the peptide chain [81, 82]. The presence of two Pro residues in the CPs sequences c(GNWHPGHKHP), c(HKHPHKHP), and c(HKHGPGHKHGPG) separates two well-defined binding domains for metal ions due to its known effect in preventing amide coordination [58, 59]. These binding pockets can be potentially designed one-by-one to furnish non-symmetric bimetallic systems (Scheme 4), [69, 72, 73, 80].

14

Scheme 4. Illustration of the number of possible domains consisting of two His in a non-Pro peptide c(HXHXHXHX) (a) and its Pro-analogue c(HXHPHXHP) (b).

Di-Pro ligands, with two equivalents of copper(II) ions, form only mononuclear complexes with exclusive imidazole donor binding under pH 6 (Scheme 4). Formation of dinuclear complexes either with or without an additional Gly residue, commences only above this pH. The peptide c(HKHPHKHP) forms the ultimate binuclear species with a different coordination pattern for each Cu(II) ion (Scheme 5) [72]. In this case the presence of additional non-His groups in the peptide cycle limits the involvement of additional amide donors and the peptide with the c(HKHGPGHKHGPG) sequence forms a di-Cu(II)-complex with a 2×{2×NIm, 2×N−am} donor set [73].

Scheme 5. Complex speciation as a function of pH for the Cu(II)/c(HKHPHKHP) and Cu(II)/c(HKHGPGHKHGPG) systems with a ligand-to-metal molar ratio of 1:2 and the associated coordination mode for each dominant compound in the system [72]. 15

Conclusions In natural systems, the same metal ion may play very different roles, e.g., as a catalytic site, an electron reservoir or a structural cofactor, which is tuned by the coordination mode. The presented modifications of cyclic peptides and their impact on Cu(II) binding indicate a great potential to apply these ligands in Cu-based systems with certain activities tuned by the design of the peptide frame. This is especially so, because the more limited structural isomerism in the case of cyclic ligands makes the resulting metal complex constructs more predictable compared to the linear analogues. Peptide cyclisation and ring expansion by means of additional non-His sequences along with their consequences indicate that rational peptide design may be applied to create a variety of cyclic peptide Cu complexes to serve different purposes. Changes in the ligand rigidity and the number and type of built-in donor groups enable the stabilization of certain oxidation states, or different metals. Moreover, dinucleating ligands may be assembled to accommodate two different metals. Such exceptional features might advance new applications including metal sensing or catalysis. This review is aimed to help understanding some design principles of homodetic cyclic peptides and in case of larger cyclic structures their domains that in turn are crucial for the future development of more complex structures capable of binding multiple metal ions. By exploiting the advancements in peptide-synthesis technology a possible direction of research may be the pending-arm extension of these basic CPs that in exchange create new metallopeptides with refined properties. The discussed principles might also pave the way toward the involvement of non-canonical amino acids that can extend the scope of applications.

Acknowledgements 16

The presented work was supported by Wroclaw Medical University (ST.D080.16.006). J. S. Pap is grateful for the Bolyai János Research Scholarship from the Hungarian Academy of Sciences.

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[73] A. Kotynia, Z. Czyznikowska, S. Bielinska, L. Szyrwiel, W. Kamysz, W. Malinka, J. Brasun, The impact of two -GlyProGly- motifs on formation of di-copper complexes by His 4-cyclopeptides, New Journal of Chemistry, 38 (2014) 5198-5206. [74] H. Kozlowski, B. Radomska, G. Kupryszewski, B. Lammek, C. Livera, L.D. Pettit, S. Pyburn, The unusual co-ordination ability of vasopressin-like peptides; potentiometric and spectroscopic studies of some copper (II) and nickel (II) complexes, Journal of the Chemical Society, Dalton Transactions, (1989) 173-177. [75] J.P. Laussac, A. Robert, R. Haran, B. Sarkar, Complexation of copper (II) with a macrocyclic peptide containing histidyl residues: novel observation of NMR spectra of paramagnetic copper (II) compounds, Inorganic Chemistry, 25 (1986) 2760-2765. [76] J. Brasun, A. Matera-Witkiewicz, S. Oldziej, A. Pratesi, M. Ginanneschi, L. Messori, Impact of ring size on the copper (II) coordination abilities of cyclic tetrapeptides, Journal of Inorganic Biochemistry, 103 (2009) 813-817. [77] A. Pratesi, G. Giuli, M.R. Cicconi, S. Della Longa, T.-C. Weng, M. Ginanneschi, Dioxygen Oxidation Cu (II) - Cu (III) in the Copper Complex of cyclo(Lys-DHis-βAla-His): A Case Study by EXAFS and XANES Approach, Inorganic Chemistry, 51 (2012) 7969-7976. [78] A. Pratesi, P. Zanello, G. Giorgi, L. Messori, F. Laschi, A. Casini, M. Corsini, C. Gabbiani, M. Orfei, C. Rosani, New copper (II)/cyclic tetrapeptide system that easily oxidizes to copper (III) under atmospheric oxygen, Inorganic Chemistry, 46 (2007) 10038-10040. [79] J. Brasun, A. Matera, S. Oldziej, J. Swiatek-Kozlowska, L. Messori, C. Gabbiani, M. Orfei, M. Ginanneschi, The copper (II) coordination abilities of three novel cyclic tetrapeptides with-His-Xaa-His-motif, Journal of Inorganic Biochemistry, 101 (2007) 452460. [80] A. Fragoso, P. Lamosa, R. Delgado, O. Iranzo, Harnessing the Flexibility of Peptidic Scaffolds to Control their Copper (II) - Coordination Properties: A Potentiometric and Spectroscopic Study, Chemistry A European Journal, 19 (2013) 2076-2088. [81] R. Bhattacharyya, P. Chakrabarti, Stereospecific interactions of proline residues in protein structures and complexes, Journal of Molecular Biology, 331 (2003) 925-940. [82] P. Chakrabarti, D. Pal, The interrelationships of side-chain and main-chain conformations in proteins, Progress in Biophysics and Molecular Biology, 76 (2001) 1-102.

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• copper binding abilities of homodetic cyclic peptides (CPs) • cyclic structure favors anchoring metal ions by the side chains • coordination properties of CPs containing different number of His residues • aspects of dinucelar copper(II) complex formation

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Justyna Brasun (born in 1973, Poland) earned PhD thesis in chemistry (2001, The coordination abilities of the peptide nucleic acids) and DSc degree (2010, The influence of the structural modifications of the oligopeptides on the metal ions binding) at the University of Wroclaw. Since 2000 she is employed at the Wroclaw Medical University and since 2011 she is a Head of the Department of Inorganic Chemistry at Faculty of Pharmacy with Division of Laboratory Medicine. Her research interest includes the development of new peptide hormone analogues showing high effectively in binding of metal ions related to radiopharmacy, designing of new molecules as models of active centers of metalloproteins, with particular focus on ability to form homo- and heteronuclear complexes.

Alekandra Kotynia (born in 1983, Poland) graduated from the Faculty of Chemistry and obtained her diploma (MSc) with specialization computer aided chemistry in 2008 at University of Wroclaw. Since 2009 she has been employed at the Wroclaw Medical University on Faculty of Pharmacy with Division of Laboratory Diagnostics. Her research focus on interaction transition metal ions like Zn2+, Cu2+ with cyclopeptides and their possible mimicking action of metalloenzymes centers.

József S. Pap: born in 1977, Hungary. Earned MSc (2001) and PhD in chemistry (2005, enzyme modeling complexes) at the Univ. Veszprém, Hungary. Worked in Poland (Univ. Wrocław, H. Kozłowski), Germany (MPI für Bioanorganische Chemie, K. Wieghardt) and the USA (Univ. Wisconsin - Madison, J. F. Berry). Between 2009-2013 worked at the Univ. Pannonia on model compounds of metalloenzymes. Leads the Surface Chemistry and Catalysis Dept., Centre for Energy Research of the Hungarian Academy of Sciences from 2013 in Budapest. His topic is water splitting by bio-inspired electrocatalysts related to renewable chemical energy storage. Married, father of two sons.