An insight into interaction of Fe2C with glycylglycine: A DFT study

Jianhua Xu

Department of Chemistry, Fuling Normal College, Fuling, 408003, China

Received 16 July 2005; received in revised form 11 October 2005; accepted 13 October 2005

Available online 15 November 2005

Abstract

This study performed at B3PW91/6-311CCG(d,p)(LANL2DZCf for Fe) level shows that the glycylglycine–Fe2C(3d6) complexes in 1I, 3H

and 5D states behave rather similarly. The ground states are all predicted to be quintet complexes. In the ground state, the most stable complex

adopts a structure in which the metal is tridentate and coordinated by two oxygen atoms and the N terminus nitrogen atom. Interestingly, the most

stable conformation of triplet states is in zwitterionic form. The charge transfer of Fe2C to glycylglycine in quintet states is less than that of single

states and triplet states. The charge transfer plays an important role in the binding process of Fe2C with glycylglycine. The main effect of the

electrostatic interaction with a continuum having the dielectric constant of water is a variation of the energy differences between these

conformations.

q 2005 Elsevier B.V. All rights reserved.

Keywords: Glycylglycine; Fe2C; Interaction; DFT

1. Introduction

Interactions of metal cations with amino acids and peptides

have attracted increasing attention in the past few years, which

is reflected in the large number of publications devoted to this

topic. This interest arises for different reasons. On one hand,

metal cation binding to peptides can induce activation effects

which, under mass spectrometry conditions, can lead to

specific fragmentations providing helpful information on the

amino acid sequence of the peptide [1–8]. Interpretation of

the mass spectra requires the accurate knowledge of the

interactions between metal cations and amino acid residues. On

the other hand, complexes of metal cations and amino acid

residues are implicated in a great number of fundamental

biological processes, such as dioxygen transport, electron

transfer, or oxidation. However, the excess concentration of

different transition-metal cations such as iron, cobalt, or nickel

is toxic. As a response of metal toxicity, living systems have

developed mechanisms of resistance based on the intracellular

complexation of the toxic metal ion by peptides such as

phytochelatins or metallothioneins, which involves the

interaction of the cation with the peptides.

These facts have motivated the experimental and theoretical

study of the activation of different amino acids and peptides by

0166-1280/$ - see front matter q 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.theochem.2005.10.008

E-mail address: xujianhua64@163.com.

metal cations. Theoretical methods allow us to study precisely

the interaction of metal cations with amino acids and small

peptides providing accurate determinations of some relevant

magnitudes, such as complexation energies. However, till now

most of the reported work has focused on the interaction of

alkali and alkaline-earth metals with glycine, the interaction of

closed shell transition-metal cations with glycine, or other

metal–amino acid systems. To the best of our knowledge, the

interaction of Fe2C with amino acids has not been considered

from a theoretical point of view.

The aim of the present work is to provide a detailed analysis

of the gas-phase binding chemistry between Fe2C cation and

glycylglycine, the simplest peptide. The ground electronic

states of Fe2C are 5D(3d6). Due to their open shell nature, the

interaction of these cations with peptides can lead to several

low-lying electronic states arising from different metal d

occupations. Moreover, depending on the degree of metal

complexation, the relative stability of different spin electronic

states could vary. Thus, in addition to the quintet states derived

from the interaction of the 5D(3d6) ground state of Fe2C, we

have also considered the triplet and singlet states that arise

from the 1I(3d6) and 3H(3d6) excited states of Fe2C.

2. Computational details

All computations are performed by using of Gaussian98

package [9]. Geometries for all structures are performed by

means of the density functional theory (DFT) with unrestricted

Journal of Molecular Structure: THEOCHEM 757 (2005) 171–174

www.elsevier.com/locate/theochem

Fig. 1. The optimized structures and selected parameters of the Fe2C-glycylglycine complexes. Bond lengths are given in angstrom. *Roman: Singlet states, Bold:

Triplet states, Italic: Quintet state.

J. Xu / Journal of Molecular Structure: THEOCHEM 757 (2005) 171–174172

Becke’s three-parameter functional (B3) [10] plus Perdew and

Wang’s 1991 (PW91) correlation functional. The double-zquality, Hay and Wadt LANL2DZ [11–13] basis sets for the

valence and penultimate shells with effective core potential for

Fe is used, and a set of the f polarization functions with an

exponent of 1.35 [14] for Fe is added. For all other atoms, the

6-311CCG(d,p) [15,16] basis sets are utilized. Zero-point

energies have also been computed in the rigid rotator–

harmonic oscillator approximation. Natural charges are

calculated by the natural population analysis at the same

level as the one used for geometry optimization.

3. Results and discussions

Glycylglycine is known to exist in neutral form in the gas

phase; the zwitterionic form is not a minimum [17–19].

However, this form can be stabilized through the interaction

with metal cations. Thus, we have considered the coordination

of the metal cation to both forms of glycylglycine. As starting

points for geometry optimizations of the neutral form, we have

considered different coordination modes that, according to

the previous works [20], maximize the metal cation–

glycylglycine interaction. Only the interaction of the metal

cation with CO2K has been considered for the zwitterionic

form. The same spin states considered for the metal cation

monohydrate systems have been computed for each complexa-

tion mode. Our results are represented in Fig. 1 and the

energetic data and NPA charges and spin densities are collected

in Table 1.

3.1. The structures of glycylglycine–Fe2C

The optimized structures and selected parameters of

glycylglycine–Fe2C are shown in Fig. 1. The relative energies

and NPA charges and spin densities on Fe atom of all

optimized structures are shown in Table 1. There are eight

structures for singlet, triplet and quintet states, respectively.

As shown in Fig. 1, the structural parameters of singlet,

triplet and quintet states are very similar. So in this section, the

structures of these conformations are concisely presented.

In conformations I and II, Fe2C ion is coordinated by three

atoms: two oxygen atoms (one from the COOH group and one

Table 1

The relative energies (Er, kcal/mol), and NPA charges (NPA)and spin densities (SD) on Fe atom of the optimized conformations of the glycylglycine–Fe2C(3d6) in

gas phase

Species Er NPA Species Er NPA SD Species Er NPA SD

1I 0.0 1.25 3I 0.1 1.33 2.07 5I 0.0 1.58 3.731II 5.1 1.25 3II 5.9 1.34 2.07 5II 5.2 1.59 3.741III 31.5 1.37 3III 21.8 1.34 2.09 5III 24.0 1.58 3.741IV 34.8 1.27 3IV 21.8 1.35 2.07 5IV 23.4 1.58 3.731V 23.6 1.42 3V 13.6 1.40 2.15 5V 11.5 1.63 3.711VI 29.0 1.43 3VI 11.8 1.47 2.09 5VI 16.7 1.64 3.711VII 40.5 1.26 3VII 9.4 1.34 2.20 5VII 21.4 1.59 3.781VIII 16.0 1.36 3VIII 0.0 1.38 2.19 5VIII 8.3 1.55 3.75

The reference energies for singlet, triplet and quintet states are K615.065217, K615.101120 and K615.147098 Hartree.

J. Xu / Journal of Molecular Structure: THEOCHEM 757 (2005) 171–174 173

belonging to the carbonyl of the peptidic group.) and the

nitrogen atom of the NH2 group (Fig. 1). Compared with

conformations I, II derives from I by a rotation of 1808 of the

OH group so that the hydrogen bond which is the traditional

hydrogen–oxygen bond observed in the carboxylic group is

destroyed. So the contribution of the hydrogen bond can be

evaluated if one compares conformations II with I.

The conformations III and IV are formed by Fe2C

coordination to a nitrogen atom of the NH2 group and oxygen

belonging to the carbonyl of the peptidic group. The hydrogen

bond is the main difference between III and IV, which is

formed by COOH group in IV and formed with the carbonyl in

COOH and NH of the peptidic group in III (Fig. 1).

In the conformations V and VI, Fe2C is coordinated by two

oxygen atoms, one from the COOH group and the other

belonging to the carbonyl of the peptidic group. In addition,

there are two hydrogen bonds in V while only one hydrogen

bond in VI; both V and VI have the one formed between

hydrogen of the nitrogen atom in peptidic bond and the

terminal nitrogen atom and the other hydrogen bond in V is the

traditional hydrogen–oxygen bond observed in the carboxylic

group. The contribution of the second hydrogen bond can be

evaluated if one compares conformations V and VI. The

conformation VI derives from V by a rotation of 1808 of the

OH group, so the hydrogen bond is destroyed.

In conformations VII and VIII, the dipeptide is in

the zwitterionic form and the cation is coordinated by the

carboxylate group. There is a hydrogen bond between

the hydrogen atom which is bonded to the nitrogen atom

(NHC3 ) and the carbonyl of the peptidic group in both the VII

Table 2

The relative energies (Er, kcal/mol), and NPA charges of Fe atom (NPA) and spin d

water solvent

Species Er NPA Species Er NPA

1I 0.46 1.45 3I 16.83 1.501II 3.51 1.42 3II 20.39 1.501III 0.00 1.58 3III 7.26 1.571IV 9.89 1.53 3IV 3.16 1.581V 11.16 1.64 3V 16.65 1.651VI 14.44 1.65 3VI 12.21 1.711VII 37.14 1.51 3VII 10.69 1.601VIII 3.66 1.60 3VIII 0.00 1.67

The reference energies for singlet, triplet and quintet states are K615.5819547, K

and VIII. The chain adopts its standard trans-configuration in

conformation VIII.

3.2. The properties of glycylglycine–Fe2C complexes

As presented in Table 1, the most stable structure for both

the singlet and quintet states is predicted to be conformation I.

In triplet state, the energy difference between conformations 3I

and 3VIII are very small. The relative energies of these

conformations vary depending on the spin state. In the singlet

state, the energy order of the different coordination modes is1I!1II!1VIII!1V!1VI!1III!1IV!1VII. The energy

order of the eight structures in triplet state is as following:3VIIIz3I!3II!3VII!3VI!3V!3IVz3III. The energy

order for the quintet state is5I!5II!5VIII!5V!5VI!5VII!5IV!5III.

The natural population analysis shows that the metal charge

is in all cases small than 1.74 and this implies that the charge

transfer plays an important role in the binding process of Fe2C

with glycylglycine. The natural charges for the singlet and

triplet states are rather close to each other (significantly lower

than the quintet). So the charge transfer is more important in

binding process of singlet and triplet states than that of quintet

sate. As shown in Table 1, the spin densities on Fe atom in

conformations I–VIII are larger than that of free Fe2C in triplet

state and in quintet state the spin densities on iron atom are

smaller than that of free Fe2C. These facts indicate that the

electron of glycylglycine in the binging process of triplet state

mainly transfer to the unoccupied d orbital of Fe2C but the

electron of glycylglycine mainly transfer to the singly occupied

ensities (SD) of the optimized conformations of the glycylglycine–Fe2C(d5) in

SD Species Er NPA SD

2.04 5I 23.18 1.70 3.77

2.04 5II 16.19 1.75 3.84

2.06 5III 4.39 1.79 3.88

2.06 5IV 0.00 1.80 3.88

2.04 5V 15.78 1.80 3.86

2.02 5VI 13.56 1.83 3.87

2.09 5VII 5.88 1.83 3.93

2.06 5VIII 10.93 1.79 3.89

615.6378581and K615.6930278 Hartree.

J. Xu / Journal of Molecular Structure: THEOCHEM 757 (2005) 171–174174

d orbital of Fe2C because the d orbitals of the quintet state

Fe2C are all occupied.

The interaction with the metal cation induces the activation

of glycylglycine bonds. However, it is worth noting that the

values of geometrical parameters of the glycylglycine moiety

do not vary considerably from one spin state to another of the

same coordination. In all the considered structures the bonds

connecting with the coordination sites are elongated obviously

due to the polarization of the Fe atom.

The most important variations among different spin sates are

observed for the metal–ligand distances. That is, the singlets

show the strongest bond between the iron cation and

glycylglycine. The reason for this behavior is the different

occupations of metal orbitals in each sates.

3.3. The solvent effects

To investigate the solvent effects, the PCM model [21]

implemented in Gaussian are used to mimic the water solvent

surroundings. The computational results are shown in Table 2.

The main effect of the electrostatic interaction with a

continuum having the dielectric constant of water is a variation

of the energy differences between the conformations. Shown

clearly in the Table 2, the most stable conformation for the

three spin states are 1III, 3VIII and 5IV, respectively.

Interestingly, the zwitterionic conformation VIII is the most

stable conformation in triplet sate.

The metal charge in water solvent is more localized on iron

atom than that of the corresponding conformation in gas phase,

respectively (Tables 1 and 2). At the same time, the charge

transfer in quintet state is not important in the binding process

because the charges on Fe2C are larger than 1.74. Similarly, the

variation of spin densities on Fe2C in binding process is also

smaller than that of the corresponding conformation in gas

phase

4. Conclusion

This study performed at a rather good computational level

shows that the glycylglycine–Fe2C(3d6) complexes in three

spin states (1I, 3H and 5D) behave rather similarly. The quintet

complexes are predicted to be the ground state. The most stable

complexes of ground and singlet states adopt a structure in

which the metal is tridentate and coordinated by two oxygen

atoms and the N terminal nitrogen atom. The peptidic chains in

these conformations depart strongly from the trans-confor-

mation of the free peptidic chains. The interaction of

glycylglycine with the metal involves an important energy

change. The energy difference between the most stable

conformation and the two following ones is slightly increased.

The charge transfer plays an important role in the binding

process of Fe2C with glycylglycine. The main effect of the

electrostatic interaction with a continuum having the dielectric

constant of water is a variation of the energy differences

between the conformations.

Acknowledgements

This work is supported by the project of science and

technology of Chongqing education council, People’s Republic

of China (No. KJ051302).

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