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Exploration of Binding Interactions of Cu with D-penicillamine and its O- and Se- Analogues in Both Gas and Aqueous Phases: A Theoretical Approach Tamalika Ash, Tanay Debnath, Tahamida Banu, and Abhijit Kumar Das J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.5b11825 • Publication Date (Web): 22 Mar 2016 Downloaded from http://pubs.acs.org on March 29, 2016
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Exploration of Binding Interactions of Cu+2 with D-penicillamine and its O- and SeAnalogues in Both Gas and Aqueous Phases: A Theoretical Approach Tamalika Ash, Tanay Debnath, Tahamida Banu, Abhijit K. Das* Department of Spectroscopy, Indian Association for the Cultivation of Science, Jadavpur, Kolkata700032, India
Abstract We have theoretically explored the entire binding phenomena of D-penicillamine and its O- and Seanalogues with Cu+2 in both gas and aqueous phases. At first, a brief conformational analysis has been performed via -XH and -COOH rotations to investigate such conformers which are suitable for binding in both bidentate as well as tridentate fashions. The stability of each bidentate and tridentate complex is determined on the basis of relative energy (∆E) and gas phase metal ion affinity(MIA) along with the bonding analysis by using Atoms in Molecule Theory. The effect of conformational change on the stability of the complexes is also examined thoroughly. By analyzing the MIA values, we have shown that the side chain substitution makes an impact on the binding process. To delve into the binding phenomena in aqueous phase, we have introduced both the first and second hydration sphere models. In first hydration sphere model, to realize the precise effect of water molecules, we have considered stable octahedral hexa-aqua copper complex, ሾݑܥሺܪଶ ܱሻ ሿାଶ and accordingly substituted water molecules depending on the bidentate or tridentate nature of the chelating agents. The influence of bulk water molecules on the energetics and geometries of the first hydrated species has also been investigated by employing second hydration sphere model assuming physiological pH through the implementation of implicit COSMO and PCM models respectively. In the second hydration sphere model, the zwitterionic structures of the amino acids and their side chain deprotonated forms are also included to study the binding phenomena with Cu+2. The complete work furnishes both the binding properties and the energetics of the copper-artificial amino acid complexes in both gas and aqueous phases which will reflect a realistic overview of the entire binding phenomena.
Keywords: Copper-artificial amino acid complex ; MIA ; COSMO ; PCM; second hydration sphere.
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1. Introduction Transition metals1-4 are useful for their chameleon-like5 behaviour as they can adopt a wide variety of co-ordination numbers, geometries and oxidation states. Understanding the nature of binding phenomena of transition metal ions with biomolecules and associated ligands is an imperative area of interest since the complexes are found to have remarkable applications in biological6-45 as well as toxicological chemistry46-51.Transition metal ions (iron, cobalt, copper, zinc etc.) are essential trace elements for human body52 present in various enzymes and hormones. However, they are also responsible for indulging toxicity when their concentration increases from marginal level. The toxicity of the metal ions can be annihilated by chelation with some specific ligands like natural and artificial amino acids48-51,53,54, nanoporous silica47, various multidentate ligands56-58, calixarene59,60 etc. Depending on the co-ordination numbers and the oxidation states of the metal ions, ligands can bind to arrest the mobility of the metal ions. The complexes formed by the metal-ligand binding are usually soluble and can easily get excreted from human body and the level of toxicity gets reduced. Detoxification processes involving metal ions and ligands are not exclusive only in living organisms as it is quite evident that chelation and complexation methods also facilitate degradation of harmful metal ions such as cadmium, mercury, lead etc. in nature. Thus, analyses of metal-ligand complex geometries, bonding patterns and electronic structures are an interesting area of research. Recent periods have witnessed a several theoretical and experimental works6-51,53-63 in order to elucidate the metal-ligand binding phenomena in various environments including detoxification processes. Zhang et al.48 synthesized poly-α,β-DL-aspartyl-L-methionine (PDM) as a novel lead chelating agent to increase the metal ion selectivity of poly aspartic acid. McAuliffe et al.61 reported the binding of both transition as well as non-transition metal ions with D/L methionine. Using different density functional methods, Sodupe and co-workers62,63 have studied the co-ordination properties of the Cu+2 with oxime analogue of glycine. They also performed the DFT (Density Functional Theory) calculation to identify the structures of Cu2+-(H2O)n complexes (n =1-6) and calculated the spin density on the co-ordinated Cu+2 metal ion by varying the methods. In our previous work57, DFT method was applied to study the complexation processes between group IIb bivalent metal ions (Zn2+,Cd2+, and Hg2+) with 3mercaptopropanoic acid to explore different co-ordination modes along with the determination of the stability of the complexes. The whole complexation phenomena were also visualized by them in implicit aqueous medium through implementation of Conductor-like Screening Solvation Model (COSMO) model. Pesonen et al.18 theoretically unveiled the binding of cysteine with alkali metals like Mg+2, Ca+2 and also with the transition metal ions e.g. Fe+3, Mn+2 and Zn+2. According to their work, cysteine is an 2 ACS Paragon Plus Environment
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interesting amino acid because of the presence of thiol group which acts as soft donor centre according to Parr and Pearson HSAB principle. As evident from their study, cysteine is able to co-ordinate with both hard and soft metal ions as it is consist with both soft S-donor as well as hard N- and O- donors. They also adopted COSMO to evaluate the aqueous phase binding processes. Spezia et al.64 reported that cobalt form very stable complexes with cysteine and selenocysteine, an Se-analogue of cysteine. They considered selenocysteine in their study to emphasize the role of selenium as chelating agent and how it acts as a potent protector against metal toxicity. Marino et al.21 structurally characterised the complexes formed by the complexation of glycine with both the bare and hydrated first row transition metal ions using DFT approach. They also used Polarizable Continuum Model (PCM) to evaluate the bulk effect on all first sphere hydrated complexes. Rulíŝek et al.30,32 studied the interaction of the side chain amino acids with Co2+, Ni2+, Cu2+, Zn2+, Cd2+ and Hg2+ to provide an quantitative idea about the affinity and selectivity of the amino acid side chains towards the metal ions. Asaduzzaman et al.65 synthesized the methyl mercury-amino acid complex along with the Se analogue and characterised the structural and electronic properties of the complexes. In the present work, we have chosen Cu+2 as the central metal ion to investigate the binding phenomena with three artificial amino acids; D-3-methyl threonine, D-penicillamine and D-3-selenyl valine, analogous to threonine, cysteine and valine respectively in both gas and aqueous phases. Copper is an essential element for human body,66 which is useful for regulating various biological activities inside the human body. It acts as a co-factor for several enzymes and also plays an important role for developing the central nervous system. However, low concentration of copper inhibits the growth of the nervous system while its excess accumulation in the body is also harmful for the health67. Wilson's disease67,68is one of the major adverse effects, which is caused by the excess copper accretion. D-penicillamine, known as an excellent chelator, is used for excretion of excess copper ion from human body68. Although the L-conformer of penicillamine is toxic in nature, the D-conformer is used in chelation therapy for the treatment of Wilson's disease. The prime interest of our work is to unveil the detailed process of complexation of D-penicillamine with Cu+2 along with its O- and Se-analogues. To do so, we have briefly performed a conformation analysis to identify the possible conformers appropriate for binding as both bidentate and tridentate chelating agents. The stability of the copper- artificial amino acid complexes in gas phase have been determined by calculating relative energy of the complexes along with the determination of gas phase metal ion affinity (MIA). The bonding properties of all the complexes in gas phase are analyzed using QTAIM (Quantum Theory of Atoms in Molecule) analysis. An analysis to detect the effect of side chain on the entire chelation process is also incorporated in our study to present the utility of the O- and Se- analogues of D-penicillamine. Moreover, we have also 3 ACS Paragon Plus Environment
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investigated the complete binding features in aqueous phase by performing both the first and second hydration sphere models, which give an overview of the entire chelation process in more realistic manner. In the calculation of first hydration sphere model, we have explicitly added water molecules to form hexa aqua copper complex and consequently substituted two or three water molecules; whereas in the second hydration sphere calculation, to visualize the effect of bulk aqueous medium, we have implicitly applied COSMO as well as PCM model to the first hydration sphere complexes. By considering the pH of the bulk aqueous medium at physiological level, we have also studied the binding phenomena of the zwitterionic forms of the amino acids with Cu+2. According to Hightower et al.69 , as binding to the metal cation via SH/SeH ends lead to produce S-/Se- by decreasing the pKa of the side chains , we have also incorporated this fact in our study. Altogether, the objective of our work is to provide a fundamental and extensive understanding of the binding properties and the energetics of the copper- artificial amino acid complexes in both gas as well as aqueous phases, which will contribute some innovative ideas to the field of metal-ligand binding.
2. Computational Details and Methodology All electronic structure calculations are carried out using the Gaussian 0970 suite of quantum chemistry program. The geometries of the free ligands and their metalated complexes are optimized by employing density functional theory (DFT) with M06-L functional in conjunction with LANL2DZ basis set for Cu+2 ion and 6-311++G(d,p) basis set for the main group elements. The combined basis set is denoted as genECP. Zhao and Truhlar71,72 have developed the M06 family of local (M06-L) and hybrid (M06, M06-2X) meta-GGA functionals that show promising performance for thermodynamic calculations without the need to refine the energies calculated by post Hartree–Fock methods. The meta-GGA M06L functional is reported to show excellent performance for energetics of the transition metal complex and is therefore strongly recommended for transition metal chemistry. Although M06L is a local functional, they are not only important to represent a more theoretically justified solution but also for practical reasons. The calculations on large complex systems by employing specialized algorithms are tens or hundreds times faster for local functionals than nonlocal ones. The basis set has been chosen following the work on the determination of metal ion affinity for biological systems, as well as the fact that a relativistic pseudopotential is essential for elements such as copper for which the non-relativistic all electron approach cannot be applied successfully. We have checked the suitability of the applied method and basis set for Cu+2 by calculating its first and second ionization potential values. The results obtained by our DFT calculation are in good agreement 4 ACS Paragon Plus Environment
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with the CCSD(T)62 and experimental results73 (see supporting information Table S1). We have also calculated the proton affinity (PA) and gas phase basicity (GB) of serine, cysteine and selenocysteine which are analogues to our titled artificial amino acids. For this case also, our calculated results obtained by using M06L/6-311++G(d,p) is very close to the experimental74 as well as theoretically64,75 reported values (see supporting information Table S2) , which clearly establish that the used method and basis set are suitable for electronic structure calculations of the aforementioned artificial amino acids. As the applied method-basis set can generate almost appropriate results, we have considered them for our entire complexation study. Metal-ion affinity (MIA) in gas phase has been computed as the negative of the enthalpy variation for the metalation process, which can be represented by the following expression Lx ( gas ) + M +2 ( gas ) → [ MLx ]+2 ( gas )
(1)
MIA(݃ܽ )ݏcan be explicitly calculated as MIA( gas ) = −{E[ MLx ]+2 ( gas ) − E[ Lx ]( gas ) − E[ M +2 ]( gas )}
(2)
Where, ܮ௫ is an artificial amino acid, x represents the number of donor centres participating in chelation (x=2 or 3) and M+2 represents the metal ion. E is the zero point corrected electronic energy obtained from self-consistent field (SCF) calculations at 0 K . In case of first hydration sphere calculations, as the entire chelation process has been done by taking Cu+2-hexa aqua octahedral complex, it can be expressed as Lx + [ M ( H 2O )6 ]+2 → [ MLx ( H 2O )6− x ]+2 + xH 2O
(3)
B.E (݂. ܽ ) ݍcan be explicitly calculated by using Gibbs Free Energy (G) as followsB.E.( f .aq ) = −{G[ MLx ( H 2O )6 − x ]+2 + x * G[ H 2O ] − G[ Lx ] − G[ M ( H 2O )6 ]+2 }
(4)
Where, ሺ݂. ܽݍሻ indicates the first hydration sphere model. The second hydration sphere calculations have also been carried out using the same level of theory as gas phase study. In this case, the self-consistent reaction field (SCRF) method has been employed using PCM76,77 and COSMO78 to calculate the effect of bulk aqueous medium on the binding properties. SCRF requests that a calculation be performed in the presence of a solvent by placing the solute in a cavity within the solvent reaction field. The PCM method creates the solute cavity via a set of overlapping spheres. COSMO is similar to the PCM as the solvent is treated as a continuum with a permittivity, ε, and therefore belongs to the continuum solvation group of models. For second hydration sphere, the B.E. is calculated by using the Gibbs Free Energy (G). Lx ( s.aq ) + [ M ( H 2O )6 ]+2 ( s.aq ) → [ MLx ( H 2O )6− x ]+2 ( s.aq ) + xH 2O ( s.aq ) 5 ACS Paragon Plus Environment
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B.E (ݏ. ܽ )ݍcan be explicitly calculated as B.E.( s.aq ) = −{G[ MLx ( H 2O )6 − x ]+2 ( s.aq ) + x * G[ H 2O ]( s.aq ) − G[ Lx ]( s.aq ) − G[ M ( H 2O )6 ]+2 ( s.aq )}
(6)
where, ሺݏ. ܽݍሻ indicates the bulk effect of aqueous medium introduced through COSMO or PCM. To elucidate the bonding phenomena, we have performed an analysis of Atoms In Molecule (AIM)79-81 using AIMall. The density functional theory (DFT) adopted here is M06-L functional in conjunction with 6-311++G (d,p) basis set for all elements. The AIM theory developed by Bader is a powerful method for analyzing the molecular structures, making a link between quantum mechanics and standard chemical concepts. This method identifies the coordinates of a particular type of saddle-point in the electron density distribution ρ(r), which is known as a bond critical point (BCP). The electronic properties which are commonly used to characterize the nature of the bonds are: the value of ρ(r) itself, the Laplacian ∇2ρ(r), Electronic Energy Density [H(r)] etc. Where, H(r)= G(r) + V(r) Where G(r) (always positive) and V(r) (always negative) are the kinetic and potential energy densities, respectively. The criterion used here to determine the nature of bonds is the ratio −G(r)/V(r). For −G(r)/V(r) > 1, the interaction is noncovalent; for 0.5 < −G(r)/V(r) < 1, it is partly covalent. In case of weak interactions, both ∇2ρ(r) and H(r) have positive values, for medium interactions ∇2ρ(r) is positive but H(r) is negative, and strong interactions have negative values for both ∇2ρ(r) and H(r).
3. Result and Discussion: We have divided the overall results and discussion into three sections. In the first section, we have done a concise conformational analysis through -XH and -COOH rotations to find out the respective conformers which are able to form bidentate and tridentate chelates. In the second part of our discussion, we have comprehensively studied the binding phenomena of the above mentioned artificial amino acids with Cu+2 in the gas phase. In the last section, we have examined the whole complexation phenomena in aqueous phase. After exploring all the binding features, we have made a comparison between the aqueous phase outcomes with the gas phase results. To make our discussion easy, we have denoted the three artificial amino acids, namely D-3-methyl threonine, D-penicillamine and D-3-selenyl valine as athr, a-pen and a-val respectively and their corresponding gas phase Cu+2 complexes as (a-thr-Cu)gas, (apen-Cu)gas and (a-val-Cu)gas. The respective first and second hydration sphere complexes, are designated as (a-thr-Cu)f.aq, (a-pen-Cu)f.aq, (a-val-Cu)f.aq and (a-thr-Cu)s.aq, (a-pen-Cu)s.aq, (a-val-Cu)s.aq respectively. The zwitterionic complexes in the second hydration sphere are represented as (a-thr-Cu) zwit.s.aq, (a-pen6 ACS Paragon Plus Environment
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Cu)zwit.s.aq, (a-val-Cu)zwit.s.aq and their side chain deprotonated complexes are as (a-thr-Cu)‾zwit.s.aq, (a-penCu)‾zwit.s.aq, (a-val-Cu)‾zwit.s.aq.
3.1 Conformational analysis The strategy we have adopted here is to locate the conformers suitable for binding with Cu+2 metal ion in both bidentate and tridentate fashions. From Scheme 1, it is noteworthy that each amino acid has total four donor centres to co-ordinate with Cu+2, i.e., N of -NH2 group, O1 (-C=O of -COOH) and O2 (-C-OH of -COOH) and the side chain X (X= OS for a-thr, S for a-pen and X=Se for a-val). Based on the side chain -XH (X= OS, S and Se) and -COOH rotations, we have identified six conformations for each artificial amino acid, denoted as A', A", B', B", C' and C" respectively (shown in Scheme 2). The energy difference among the conformers is presented by the relative energy (∆Econf). The ∆Econf values for all the conformers of three artificial amino acids in both gas and aqueous phase are reported in Table 1. As depicted in Table 1, the energy difference among the conformers varies within ~2.8 kcal/mol, ~1.8 kcal/mol and ~1.9 kcal/mol for a-thr, a-pen and a-val respectively in gas phase whereas in aqueous phase the difference becomes ~1.5 kcal/mol, ~2.1 kcal/mol and ~ 2.3 kcal/mol for COSMO and ~1.9 kcal/mol, ~2.1 kcal/mol and ~ 2.3 kcal/mol for PCM. Therefore, the energy differences among the conformers are significantly low to allow their presence with equal preference in both gas and aqueous phases.
O NH2
C
XH
HO
H
H3C
CH3
Scheme 1. Schematic diagram of the titled artificial amino acids, where X= OS, S and Se. The arrows represent the rotation of –XH and –COOH. The co-existence of all the conformers in both gas and aqueous phases indicates that all the conformers can participate in the complexation phenomena. It is observed that a particular type of binding mode can be obtained from different conformers. But as the energy difference among these conformers is sufficiently low, all the binding modes will participate in binding with Cu+2. The respective bidentate and tridentate binding modes obtained for each conformer are also presented in Table 2 where we have 7 ACS Paragon Plus Environment
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shown that only C' and C'' conformers are found to be suitable for forming tridentate complexes with Cu+2. Scheme 2 represents how all the six conformers are obtained through the -XH and -COOH rotations. Rotation of -XH generates three positions
B
A
C
-COOH rotation
-COOH rotation
A'
A"
-COOH rotation
B'
B"
C'
C"
Scheme 2. Flow chart of all possible conformers of the artificial amino acids obtained through rotation of –XH and –COOH.
Table 1. Relative Energies (∆Econf) of a-thr, a-pen and a-val conformers in gas phase/COSMO/PCM in kcal/mol.
a-thr
∆Econf
conformers gas/COSMO/PCM
∆Econf
a-pen conformer
a-val
∆Econf
gas/COSMO/PCM conformers gas/COSMO/PCM
A'_thr
2.84/0.95/1.72
A'_pen
1.73/0.41/1.15
A'_val
1.18/0.09/0.84
A"_thr
2.61/1.45/1.94
A"_pen
1.77/0.99/1.55
A"_val
1.37/0.76/1.27
B'_thr
0.00/0.23/0.25
B'_pen
1.31/1.45/1.69
B'_val
1.70/1.58/1.87
B"_thr
0.08/0.41/0.40
B"_pen
1.60/2.07/2.07
B"_val
1.93/2.32/2.27
C'_thr
0.19/0.00/0.00
C'_pen
0.00/0.00/0.00
C'_val
0.00/0.00/0.00
C"_thr
1.18/0.39/0.69
C"_pen
0.85/0.16/0.65
C"_val
1.16/0.54/0.89
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Table 2. Respective binding modes of a-thr, a-pen and a-val conformers.
a-thr conformers
Binding modes
a-pen
Binding modes
conformers
a-val conformers
Binding modes
A'_thr
NO1,NOS
A'_pen
NO1,NS
A'_val
NO1,NSe
A"_thr
NO2,NOS
A"_pen
NO2,NS
A"_val
NO2,NSe
B'_thr
NO1,O2OS
B'_pen
NO1,O2S
B'_val
NO1,O2Se
B"_thr
NO2,O1OS
B"_pen
NO2,O1S
B"_val
NO2,O1Se
C'_thr
NO1,O2OS,NO1OS
C'_pen
NO1,O2S,NO1S
C'_val
NO1,O2Se,NO1Se
C"_thr
NO2,O1OS,NO2OS
C"_pen
NO1,O1S,NO2S
C"_val
NO1,O1Se,NO2Se
3.2 Gas Phase Binding Properties In this section, we are going to discuss the gas phase binding properties of the aforementioned copperartificial amino acid complexes. We have identified total fourteen stable complexes for each artificial amino acids; among them two are tridentate complexes and rest of the complexes are bidentate in nature. On the basis of the mode of coordination, the complexes are divided into seven categories; those are NO1X gas, NO1gas, O1Xgas, NXgas, NO2X gas, NO2gas and O2Xgas respectively. Each bidentate complex is obtained twice or thrice based on its conformational changes and in this way total fourteen complexes are formed. The stabilities of these are measured by calculating the relative energies (∆E) along with their gas phase MIA values, which are presented in Table 3. It is evident from Table 3 that the tridentate C'_NO1Xgas (where, X= OS, S and Se), where the Cu+2 metal ion is coordinated through its N, O1 and X donor centres, is found to be the most stable complex for all three artificial amino acids. In case of bidentate complexes, it is observed that, for (a-thr-Cu)gas, the B"_O1OS gas complex (263.08kcal/mol) and for (a-val-Cu)gas, B'_NO1gas (281.06kcal/mol) has the highest MIA value whereas for (a-pen-Cu) gas, both the B"_O1Sgas and B'_NO1gas have almost equal MIA values (270.86 kcal/mol and 269.9 kcal/mol respectively). On the other hand, in case of NXgas complexes where N donor centre and side chain X donor centres are participated, for (a-thr-Cu)gas , A"_NOSgas has less ∆E and higher MIA value than A'_NOSgas whereas for (a-pen-Cu)gas and (a-val-Cu)gas, both the complexes have nearly same ∆E as well as MIA values. In case of O2 coordinated complexes, for (a-thr-Cu)gas, the tridentate C"_NO2OSgas has 9 ACS Paragon Plus Environment
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the maximum stability followed by the NO2gas and O2Xgas category of complexes while for the other two cases the tridentate C"_NO2Xgas and bidentate NO2gas complexes have almost similar MIA values. It is noted that all the complexes where O1 (e.g. NO1Xgas, O1Xgas, NO1gas) is participated in bonding, the MIA values are higher compared to the complexes where O2 (e.g. NO2Xgas, O2X gas, NO2gas) is involved. It is also evident from our study that a particular binding mode (e.g. NO1gas) can be obtained several times from different conformers (for A', B' and C') and the complexation with Cu+2 metal ion leads to the formation of different complexes (e.g. A'_NO1gas, B'_NO1gas and C'_NO1gas) having different MIA values. Therefore, from the perspective of thermodynamic stability, it can be articulated that the complex having least relative energy is the most stable complex. Nevertheless, the complexes having higher ∆E values must also be considered in the chelation process as they have also significant MIA values. It is noticeable that the MIA values of the complexes increases from (a-thr-Cu)gas to (a-pen-Cu)gas to (aval-Cu)gas as a result of substitution whether the side chain is directly participating in bonding or not. In case of direct bonding, this phenomenon can be explained from the perception of geometrical features and the participating orbitals. The binding modes associated with the X donor centres lead to the formation of five- and six-member rings during chelation with Cu+2. Although chelations through fiveand six-member ring formation are stable enough, ring strain may appear due to geometrical constrains. In case of (a-thr-Cu)gas, the ring strain arises mainly due to the angle strain which is being reduced by substitution of OS by S followed by Se. Relaxation of the angle strain ongoing from (a-thr-Cu)gas to (apen-Cu)gas to (a-val-Cu)gas can be explained from the perspective of participating orbitals of X which are 2p, 3p and 4p respectively. As the size of the contributing orbital increases from OS to S to Se, the interatomic bond distances connecting the Cu+2 with OS, S and Se also increases (~2.0 Å to ~2.28 Å to ~2.38 Å respectively), which leads to increase the flexibility of the ring by decreasing the angle strain. Therefore, this ring strain is reduced in (a-pen-Cu)gas and finally it almost disappears in (a-val-Cu)gas. Therefore, in case of direct binding, the increased values of MIA from (a-thr-Cu)gas to (a-pen-Cu)gas to (a-val-Cu)gas can be well understood by the stabilization of the whole complex acquired by the reduction of ring strain. The effect of side chain substitution is not only pronounced in direct binding but also in both indirect NO1gas and NO2gas complexes where XH is not directly participating in bonding, causes a gradual rise of MIA value from (a-thr-Cu)gas to (a-pen-Cu)gas to (a-val-Cu)gas. Although the proper reason behind this is yet to be unveiled, it may be explained in terms of increased electron density in the overall complex as a result of substitution of side chain OS by S and Se respectively. The greater electronegativity of OS than S and Se makes the whole complex as well as the donor centres more 10 ACS Paragon Plus Environment
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The Journal of Physical Chemistry
electron deficient in O-analogue compared to the other two analogues, which in turn causes a decrease of the MIA value in (a-thr-Cu)gas complexes.
Table 3. Relative Energies (∆E) and the respective MIA values of (a-thr-Cu)gas, (a-pen-Cu)gas and (a-valCu)gas complexes in gas phase in kcal/mol.
(a-thr-Cu)gas
∆E
MIA
(a-pen-Cu)gas
∆E
MIA
(a-val-Cu)gas
∆E
MIA
C'_NO1OSgas
0.00
264.14
C'_NO1Sgas
0.00
272.79
C'_NO1Segas
0.00
281.46
B"_O1OSgas
0.94
263.08
B"_O1Sgas
3.53
270.86
B"_O1Segas
6.45
276.94
C"_O1OSgas
3.66
261.47
C"_O1Sgas
6.58
267.05
C"_O1Segas
10.19
272.44
A'_NO1gas
8.27
258.51
A'_NO1gas
5.61
268.9
A'_NO1gas
4.53
278.06
B'_NO1gas
9.44
254.5
B'_NO1gas
4.19
269.9
B'_NO1gas
2.10
281.06
6.84
274.63
C'_NO
1
9.48
254.65
C'_NO
A'_NOSgas
12.69
254.09
A"_NOSgas
7.93
C"_NO2OSgas
1
1
7.85
264.93
C'_NO
A'_NSgas
9.82
264.69
A'_NSegas
10.73
271.85
258.62
A"_NSgas
8.91
265.64
A"_NSegas
10.67
272.16
11.17
253.96
C"_NO2Sgas
10.64
263.00
C"_NO2Segas
11.02
271.61
A"_NO2gas
19.20
247.35
A"_NO2gas
17.88
256.67
A"_NO2gas
15.21
267.63
B"_NO2gas
16.24
247.78
B"_NO2gas
8.72
263.67
B"_NO2gas
5.65
271.74
C"_NO
gas
2
gas
2
gas
2
gas
17.93
247.19
C"_NO
gas
13.05
260.59
C"_NO
gas
10.78
271.85
B'_O2OSgas
17.60
246.34
B'_O2Sgas
18.83
255.27
B'_O2Segas
22.44
260.73
C'_O2OSgas
18.45
245.68
C'_O2Sgas
22.46
250.32
C'_O2Segas
26.00
255.46
3.2.1 Bonding Analysis The bonding properties of the neutral complexes are analyzed by AIM analysis taking the gas phase structures. The calculated AIM parameters are reported in Table S5, S6 and S7 (see supporting information). As evident from the tables, positive and low ∇2ρ(r) values at the BCP of the respective LCu+2 bonds indicate a depletion of electron density, which is a characteristic of the closed shell interaction. It is also found that for (a-pen-Cu)gas and (a-val-Cu)gas, the ∇2ρ(r) values for N-Cu+2 and O1Cu+2 bonds are greater than S/Se-Cu+2 and O2-Cu+2 bonds whereas for (a-thr-Cu)gas, the ∇2ρ(r) of OSCu+2 bond is almost same as O1-Cu+2 and greater than N-Cu+2 and O2-Cu+2 bonds. Moreover, the values of the total energy density, H(r), are negative for all the above mentioned bonds. According to Koch and 11 ACS Paragon Plus Environment
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Popelier81, if ∇2ρ(r) >0 and H(r) 0 and H(r)
