Electronic Structure of Biotin Conformers Studied with SAC-CI and

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Electronic Structure of Biotin Conformers Studied with SAC-CI and OVGF Methods Fatemeh Abyar, and Igor Novak J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b12631 • Publication Date (Web): 31 Jan 2018 Downloaded from http://pubs.acs.org on February 1, 2018

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The Journal of Physical Chemistry

Electronic Structure of Biotin Conformers Studied with SAC-CI and OVGF Methods

F. Abyar a,*, I. Novak b

a

Chemical Engineering Department, Faculty of Engineering, Ardakan University, Ardakan, Iran, 89518-95491

b

Charles Sturt University, POB 883, Orange, NSW 2008, Australia

Corresponding author: [email protected] , [email protected] (F. Abyar) Telephone Number: 98353223240923 Fax Number: 983532248384

ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract In this work, the study was performed of thirty seven gas-phase conformers of biotin and two biologically active conformers of biotin in the ligand-receptor complexes with astavidin and streptavidin. The ionization energies and photoelectron spectra of conformers were calculated by two methods: general-R symmetry adapted cluster-configuration interaction (general-R-SAC-CI) method and outer-valence Green's function (OVGF) method. The photoelectron spectrum of each conformer was calculated using the basis set D95 (df,pd) for both methods. The simulated photoelectron spectra of free molecules and bio-active conformers calculated by the two methods were compared. Natural Bonding Orbitals (NBO) calculations were also performed for the assignment of ionization bands of each conformer. NBO calculation indicated that first to five ionization bands correspond to ionizations from orbitals localized in the two rings. The most important point about the ionization of all conformers is that the removal of electron from the σ bonding orbital (C-S) takes place above 10.0 eV


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1.

Introduction B7 vitamin known as biotin, has eight different forms but only one of them is biologically

active. For example, D-biotin is biologically active while its L-form is not1. Biotin has important role in cell growth and when bound to proteins acts as coenzyme for carboxylase enzymes which are involved in fatty acid synthesis, gluconeogenesis and other biochemical processes. Also, biotin acts as coenzyme with acetyl-CoA carboxylase for catalyzing carbon dioxide fixation reactions. The structure of biotin consists of carboxyl group-containing side chain and two rings consist of imidazolidine-2-one and tetrahydrothiophene rings which are labeled A and B, respectively in Figure 12. The molecular structure and conformation of biotin has been determined experimentally in the solid state by X-ray diffraction conformations when bonded to protein receptors

4,5

3

as well as in bio-active

. Biotin-protein complex has the strongest

known ligand-protein binding constant in molecular biology which makes the investigation of its electronic structure especially interesting. Vitamins have many isomers which includes conformers and tautomers with different biological properties. Therefore, conformational analysis of vitamins is very important. Fraschetti et al investigated structure and conformation of protonated D-(+)-biotin by combined computational and Infrared Multi photon Dissociation (IMD) methods in gas phase. They found that this compound has folded structures and with one structure predominating 6. In the other work, Strzelczyk et al. have shown that only folded conformers which formed intermolecular hydrogen bonds are stable in the gas phase 7. To the best of the authors’ knowledge, there is no comprehensive study of conformers of biotin. In this work, thirty seven gas phase conformers of



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biotin were investigated by Density Functional Theory (DFT) together with two conformers which were found to be biologically active (in ligand-receptor complex). The knowledge of the electronic structure of vitamins (especially their valence ionization energies) is important for understanding their biological activity. The photoelectron spectroscopy (UPS) is one of the best methods for studying the electronic structure of molecules

8,9,10

. The

most challenging part of gas phase photoelectron spectroscopy of biomolecules is the possible decomposition and degradation of sample during measurement. This is why there are no reported UV photoelectron spectra (and ionization energies) for many biologically important molecules in gas phase. Accurate computational methods can be used to simulate UPS and obtain valence ionization energies. The high-level quantum chemical calculations based on the general-R symmetry adapted cluster-configuration (general-R-SAC-CI) and outer-valence Green's function (OVGF) methods provide good description of valence ionization processes. Despite many investigations on chemical and structural properties of biotin, there are no literature data on its ionization energies or photoelectron spectra. As a continuation of our earlier work 11,12,13,14 the ionization energies were calculated and photoelectron spectrum simulated for conformers of biotin by using general-R-SAC-CI and OVGF methods.

2.

Computational Methods In this work, the quantum chemical calculations were performed using the Gaussian 09

Quantum Chemistry Package

15

. According to the data on the PubChem web site, biotin has

thirty seven conformers in the gas phase 16. The geometries of these conformers were optimized


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in the gas phase using density functional theory (DFT) at B3LYP/6-31+G(d) level (See Figure S1). In order to obtain their Boltzmann Population Ratios (BPRs) standard Gibbs free energies of conformers of biotin were also calculated at the same level of theory. It was found that seven conformers are populated in the gas phase (see Figure 1). The ionization energies of the selected conformers were calculated with general-R-SAC-CI

17,18,19,20,21,22,23

and OVGF

24

methods. The

calculations were performed by same basis set that D95 (df,pd) basis set used in both methods. The intensities of ionization bands were estimated by the monopole approximation in the general-R-SAC-CI method

25

, which allows the correct evaluation of relative intensities of

ionization bands in molecules. The use of OVGF method is well established in UV photoelectron spectroscopy and provides the ionization energies which agree with experimental results to better than ±0.5 eV. The accuracy of simulated PE spectra of biotin can be gauged by comparison with the experimental spectra of its composite parts (i.e. by employing an orbital interaction model such as the composite molecule method, CMM). The experimental ionization energies give an indication of how accurate our calculated ionization energies of biotin may be. Biotin contains two moieties: tetrahydrothiophene and imidazolidine-2-one whose photoelectron spectra were measured

26,27

and the relevant ionization energies are included in Table 1. It appears that SAC-

CI method generally underestimates the valence ionization energies of biotin. The natural bonding orbital (NBO) calculations were also performed at the DFT level of theory using D95 (df, pd) basis set to determine contributions of different natural bonding orbitals in the canonical molecular orbitals involved in the ionization processes which is required for spectral band assignment. The NBO calculations were performed using NBO (version 6) 28.



A

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B

III

II

I

7.5٪

11٪

11.5٪

IV

V

VI

VII

21٪

6٪

15.5٪

6٪

Figure 1 The optimized structures of the populated conformers of biotin. The percentages of the population of conformers have been obtained in the gas phase.


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3. Result and Discussion 3.1 Selection of the Basis Set

There are no reported experimental photoelectron spectra of biotin, to the best of the authors’ knowledge. Therefore, the suitability of the selected basis set (D95 (df,pd)) was investigated by two computational methods. The NBO calculations show that first ionization takes place from the lone pairs of S atom located in tetrahydrothiophene ring (ring B in the Figure 1). The values of ionization energies calculated for tetrahydrothiophene by SAC-CI was about 8.18 and 8.29 eV by OVGF method. Tetrahydrothiophene has ionization energy of about 8.41 eV that has reported by Kuhn et al.

27

. The lowest valence ionization energies of

tetrahydrothiophene as calculated by the two methods are in good agreement with the measured ionization energy of tetrahydrothiophene (see Table 1). This suggests that our theoretical methods are suitable for predicting ionization energies and simulating UV photoelectron spectrum of biotin. 3.2 Ionization Energy and Simulated Photoelectron Spectroscopy of Biotin

As mentioned before, thermochemistry calculations performed in this work, showed that only seven conformers are stable in the gas phase. The calculated photoelectron spectrum of conformers of biotin by SAC-CI and OVGF methods were shown in Figure 2 ( (a) SAC-CI were indicated with solid lines and (b) OVGF were shown with dash lines). Vertical lines show the energy positions of the calculated ionization bands obtained by the two methods. Comparison between two calculated photoelectron spectra for all conformers is shown in Figure 3a. Energy deference between SAC-CI and OVGF calculated ionization with experiment values show that OVGF calculation has more agreement with experiment (see Table. 1). So, for adjusting the position of the first peak of the OVGF calculated spectrum vs. the first peak of the SAC-CI



calculated spectrum, SAC-CI spectrum was shifted towards higher ionization energies with energy shifts varying between 0.35 and 0.5 eV. To simulate the photoelectron spectrum of biotin, the Boltzmann-weighted photoelectron (BWP) of conformers were summed up which were shown for two methods in Figure 3b. The seven ionization energies and the corresponding band intensities obtained with two methods are given in Table. 1. Also, pole strengths are presented and can be seen that all are between 0.9-0.92, which is consistent with a one-electron depiction of ionization

29,30,31

. Main Electronic Configuration (MEC) and assignment spectral for five

ionization bands were summarized in Tables S1-S7. Also Figures S2 to S8 present shapes of canonical molecular orbitals involved in the first five ionization bands of conformers. 3.2.1 Photoelectron Spectra of Conformers Conformer I

The ionization energies and corresponding band intensities are shown in Table 1. The lowest energy band in the calculated OVGF spectrum comprises only one ionization. As shown in the Figure 3a, SAC-CI spectrum has been shifted to higher binding energy by 0.35 eV to match the OVGF simulated spectrum. After the energy shift, the first ionization energies of conformer I calculated by the two methods are very similar. The OVGF calculation gives seven ionization bands in the simulated photoelectron spectra, but only five features in SAC-CI simulation. As shown in Figure 2a, first feature of SAC-CI comprises two ionizations related to removing electrons from highest occupied molecular orbital (HOMO) (No.65 orbital) and HOMO-1, respectively. The first ionization band of conformer I is related to the ionization from HOMO orbital. Table S1 also shows that ionization occurs from the lone pairs on sulfur in the five member ring (ring B). Shape of this orbital is shown in Figure S2.


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Table 1 Ionization energies (IE) of conformers of biotin and fragment molecules such as tetrahydrothiophene and imidazolidine-2-one calculated by SAC-CI and OVGF with the same basis set. The experimental values of ionization energies of relevant components of biotin (tetrahydrothiophene and imidazolidine-2-one) taken from references 26, 27 are also given.

Conformer

I1(eV)

I2

I3

I4

I5

I6

I7

I

8.19 a(0.81)b 8.67c( 0.905)d

8.38 (0.80) 9.53 ( 0.902)

8.77(0.79) 9.99(0.896)

9.19 (0.78) 10.85 (0.899)

10.11(0.80) 11.2(0.897)

10.44(0.79) 11.5( 0.90)

11.29 (0.81) 11.86(0.901)

II

8.03(0.81) 8.6

8.24(0.80) 9.47

8.68(0.803) 9.92

9.10 (0.79) 10.79

10.23(0.81) 11.17

10.64(0.81) 11.41

10.77 (0.81) 11.78

III

8.16(0.81) 8.66

8.32(0.81) 9.52

8.76(0.81) 9.97

9.15(0.78) 10.83

10.32(0.81) 11.21

11.05(0.81) 11.42

11.97(0.80) 11.98

IV

8.16(0.81) 8.67

8.36(0.80) 9.53

8.79(0.80) 9.97

9.17(0.78) 10.84

10.41(0.81) 11.24

10.94(0.80) 11.4

11.81(0.81) 12.03

V

8.249(0.81) 8.81

8.61(0.80) 9.77

8.84(0.80) 9.95

9.28(0.78) 10.94

10.41(0.80) 11.32

10.97(0.80) 11.36

11.38(0.81) 12.12

VI

8.06(0.81) 8.61

8.27(0.80) 9.48

8.70(0.80) 9.93

9.13(0.78) 10.8

10.28(0.81) 11.19

10.80(0.81) 11.44

11.81(0.81) 11.77

VII

8.08(0.81) 8.61

8.31(0.80) 9.49

8.72(0.79) 9.95

9.14(0.78) 10.81

10.19(0.81) 11.16

10.78(0.81) 11.53

11.22(0.81) 11.66

7.97 8.60 c

8.40 9.59

8.62 9.64

8.91 10.57

10.30 11.26

10.46 11.58

11.40 11.71

7.99a 8.83 c

8.13 9.32

8.33 9.74

10.47 11.38

10.99 11.61

11.67 11.92

8.18 a 8.37 c 8.41e (nS) 9.48 a 9.5c (π-) 9.6e

10.65a 10.61c 9.50a 9.75c ( π+) 9.89e

11.588a 11.82c 11.38e (σ) 9.93a 10.38c (nO) 10.33e

11.869 12.00c

12.067 12.18

12.312 12.42

13.665 13.84

13.50a 13.38c 13.4e

13.79 13.96

14.11 14.25

14.37 14.66

Bioconformer avidin Bioconformer streptavidin Tetrahydrot hiophene imidazoline2-one a

8.63 10.00

Calculated IEs at the SAC-CI/D95(df,pd) method, b Intensity of ionization with SAC-CI theory

c

Calculated IEs with OVGF with the same basis set, d Pole strength of the intensities is between 0.91-0.92 so were not included in the table. e

The experimental values of ionization energies of relevant fragment molecules: tetrahydrothiophene and imidazolidine-2-one taken from refs. 26, 27



14

a)

b)

Intensity (arb.uni)

12

VII

VII

VI

VI

Intensity (arb.uni)

10

V 8

IV 6

III

V IV III

4

II

II

2

I I

0 8

9

10

11

12

8

Binding Energy (eV)

9

10

11

12

Binding Energy (eV)

Figure 2 The calculated photoelectron spectra of all conformers of biotin (a) SAC-CI (solid lines) (b) OVGF (dash lines). Vertical lines show the energy positions of the calculated ionization bands. a) b)

VII

OVGF

SAC-CI

VI

Intensity (arb.uni)

Intensity (arb.uni)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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V IV III

II 8

9

10

11

I

12

Binding Energy (eV)

8

9

10

11

12

Binding Energy (eV)

Figure 3 (a) Comparison between the SAC-CI calculated photoelectron spectra of conformers (solid lines) with their simulated photoelectron spectra obtained with OVGF method (dash lines) (arrangement of conformers are same Figure 2). (b) The calculated Boltzmann-weighted photoelectron (BWP) spectrum of conformers which labeled with SAC-CI and OVGF.


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The second ionization band occurs from HOMO-1 which has nonbonding character, and corresponds to the linear combination of nitrogen lone pairs in ring A. The second ionization energy is higher in the OVGF calculation. Third ionization band is from HOMO-2 which is linear combination of nitrogen lone pairs and π C=O orbital of ureido group of ring A. The fourth ionization originates from HOMO-3 related to the oxygen lone pair in carbonyl group of ring A. The MO corresponding to the fifth ionization band is a linear combination of two single ionized HF determinants related to HOMO-4 (major contribution) and HOMO-5. HOMO-4 is mostly related to the lone electron pairs of sulfur and σ (S 1- C 9) bond while HOMO-5 is mainly from oxygen lone pair on C=O of COOH group and σ bonds of S 1C10 and C15‒C 16. The shapes of some canonical molecular orbitals of conformer I confirm that the most probable of ionization occurs from these. The Koopmans’ approximation states that ionization energy approximately equals the negative value of HF molecular orbital energy 32. The approximation does not include effects of electron correlation or electron reorganization which are important in determining the final value of ionization energy. SAC-CI and OVGF consider electron correlation therefore it may breakdown of the implied Koopmans’ theorem in the ionization process. It is notable that the fifth ionization energy exhibits non-Koopmans’ behavior while the Koopmans’ approximation is valid for the first four ionization bands. Conformer II

The calculated SAC-CI spectrum of this conformer consists of five features while its OVGF spectrum gives six features (see Figure 2a and b). The second and fifth peaks in the SACCI spectrum of conformer II comprise two ionizations while OVGF spectrum predicts a single ionization relevant for the fourth peak. As shown in Figure 2b OVGF simulated spectrum of



conformer II has one feature less than conformer I. The first vertical ionization band of this conformer is shifted towards lower ionization energy in comparison with SAC-CI spectrum of conformer I while an OVGF spectrum predicts nearly the same ionization energy for the two conformers. The energy separation between the first and second ionization bands in conformer II is higher than conformer I according to the OVGF calculations (see Figure 2b). The calculated spectrum of SAC-CI has been shifted towards higher binding energy (by about +0.48 eV) to match the position of the first calculated ionization band in the calculated OVGF spectrum. There appears to be a good agreement between the shifted ionization energies obtained by OVGF with calculated SAC-CI spectrum. The first ionization band is due to the ionization from HOMO orbital (Table S2). HOMO orbital originates from S atom in five member ring, similar to the assignment of conformer I. The MEC of the second ionization takes place from HOMO-1, related to lone pairs of nitrogen atoms. The third band corresponds to ionization from orbital which can be described as a linear combination of two single ionic HF determinants of HOMO-2 and HOMO-4 with different contributions (Table S2). This ionization takes place from different sites in conformer II while in conformer I it happens from HOMO-3 orbital that is mostly localized on the ring A. The fourth ionization band is related to the ionization of the electron from HOMO-3 (oxygen lone electron pairs of COOH group). Therefore, the assignment of the fourth ionization band is similar to conformer I. (see Table S2). Similar to conformer I, fifth ionization band is related to linear combination of HOMO-2 and HOMO-4 orbitals with the nonbonding character due to lone pairs on N and O atoms. It is interesting to notice that third and fifth ionization bands correspond to ionization of orbitals composed of the same linear combination with different contributions. The seventh ionization band is shifted to lower energy in the two methods, but more so in OVGF than SAC-CI method.


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Koopmans’ approximation is valid for the first, second and fourth ionization bands but not for third and fifth ionization bands. Comparison between Table S1 and S2 confirms that the extent of electron correlation/relaxation is more significant in conformer II than conformer I because of the failure of Koopmans' theorem for conformer II. Conformer III

Comparison the spectra of conformer III with conformers I and II show that the simulated spectra are shifted to higher binding energies as predicted by the two computational methods. The calculated SAC-CI spectrum has been shifted as +0.43 eV to match OVGF spectrum (see Figure 3). It can be seen from Figure 2 that the density of ionic states (DOS) of conformer III is lower than for conformers I and II so the gap in energy between the ionic states of conformer III is larger than for conformers I and II. The simulated spectra of conformer III consists of six features as predicted by both OVGF and SAC-CI methods (unlike the prediction for conformer II). In SAC-CI spectrum, the first peak is due to the two ionizations while the remaining peaks correspond to single ionizations. The fifth feature in OVGF spectrum consisted of two ionizations. The MECs of the ionic states of conformer III are same as those of conformer II and are not discussed further. Figure 3 shows that the seventh ionization band of this conformer is shifted to higher binding energy as predicted by both methods. Also, the breakdown of Koopmans’ approximation for the third and fifth ionization is similar to conformer II. The canonical molecular orbitals of the conformer III corresponding to the first five ionizations are shown in Figure S4. Conformer IV

The simulated photoelectron spectrum of this conformer is shown in Figure 2. As seen in Figure 2, the shape of the calculated photoelectron spectrum of conformer IV is very similar to



conformer III with negligible difference in ionization energies. The difference between conformer III and IV is related to the rotation around C15-C16 bond. Similar to conformer III, the first ionization band of conformer IV corresponds to the ionization from HOMO, which is a nonbonding molecular orbital (Table S4). Figure S5 shows that HOMO is mostly localized on sulfur atom in the ring B. The main electronic configuration of the second ionic state of this conformer is similar to conformer III with little difference in contributing orbitals (see Table S5). The third ionization band is a linear combination of HOMO-2 and HOMO-4, with HOMO-2 having major contribution. The MEC of the fourth ionic state occurs from oxygen atom of ring A which is related to the ionization from HOMO-3 orbital. The MEC of the fifth ionic state is a linear combination of two HF determinants related to the ionization from HOMO-2 and HOMO4 with the main contribution in the linear combination being provided by HOMO-4. It can be seen from Table S4, that percentages of molecular orbitals in linear combinations are unlike that of conformer III. The shapes of the molecular orbitals of conformer IV have been shown in Figure S5. Similar to conformer III and I the Koopmans’ approximation breaks down for third and fifth ionization bands. Conformer V

The calculated photoelectron spectra of this conformer are different from other conformers. As seen in Figure 2, there are six and five distinguishable peaks in the calculated photoelectron spectrum according to SAC-CI and OVGF methods, respectively. Comparison between previous OVGF spectra with the OVGF spectrum of conformer V show that spectrum of conformer V is shifted to the higher ionization energies. On the other hand, SAC-CI calculation predicts peak position similar to conformer I. Also, the energy gap between the second and third ionization bands of conformer V is smaller than in others. The SAC-CI


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spectrum was shifted to higher binding energy (by +0.5 eV) to achieve the best agreement with the OVGF spectrum. Similar to the spectra of previously described conformers, the first ionization band of conformer V corresponds to ionization from HOMO which has sulfur lone pair character. (see Tables S5 and Figure S6). As mentioned earlier, the first ionization energy of this conformer is higher than others which means that its HOMO has lower energy than in other conformers. It is notable that the second ionization band originates mostly from HOMO-1 whose assignment is different from other conformers. HOMO-1 has nonbonding character has lone pair character localized at N5 unlike in other conformers where electron was removed from orbitals which were linear combinations of N5 and N6 lone pairs (see Tables S1 to S5). The third ionization in conformer V should take place from HOMO-2 according to Koopmans’ theorem, but it actually corresponds to ionization from orbital which can be described as a linear combination of three HF canonical (single determinant) orbitals HOMO-1, HOMO-2 and HOMO-3 when electron correlation is included. It is opposite to the MEC of pervious conformers. The main electronic configuration relevant to the fourth ionization band is a linear combination of three HF single determinant HOMO-2, HOMO-3 and HOMO-4 wavefunctions, unlike in other conformers. HOMO-2 predominates in the wave function of the fourth ionic state of other conformers. This implies that the extent of electron correlation in the fourth ionic state of conformer V is larger than in other conformers. Ionization in fourth band takes place mostly from ring A and B localized orbitals. Similar to other conformers, fifth ionization band pertains to a linear combination of HF single determinant wavefunctions related to HOMO-4 and HOMO-2 (HOMO-4 being the major contribution). It is possible that ring A ruptures in the course of this ionization because it corresponds to the removal electron from predominantly σ bonding orbital (S 1- C 9) with some sulfur lone pair character. It is evident from Table S5 that



the Koopmans' theorem breaks down for the third, fourth and fifth ionization bands in this conformer. The role of electronic correlation/reorganization is very important in these ionic states. Conformer VI

The simulated photoelectron spectrum of conformer VI is different from the spectrum of conformer V and has some similarities to other conformers (see Figure 2 and 3). This spectrum contains six features with intensity ratio 2:1:1:1:1:1: according to SAC-CI method. The OVGF simulated spectrum also consists of six features with only the fifth feature having double intensity. As shown in Figure 3a, SAC-CI spectrum was shifted by +0.41 eV to higher ionization energies to match OVGF spectrum. The first ionization takes place from HOMO with sulfur lone pair character. It seen that the assignment of the first ionization band is thus the same as for other conformers. The MEC of the second ionization band is HOMO-1 which has nonbonding character related to nitrogen atoms of ring A. The wave function of the third ionic state is a linear combination of HOMO-4 and HOMO-2 (the latter having major contribution). HOMO-2 is mostly composed of the lone electron pair at N5 atom and C=O carbonyl group in ring A. The wave function of the fourth ionic state of conformer VI corresponds to HOMO-3. HOMO-3 has nonbonding character due to oxygen lone pairs of COOH (oxygen atom of carboxyl bond on the ring A). Finally, the fifth ionization band is similar to the third ionization band with the contribution of the determinants related to HOMO-2 and HOMO-4 but now with HOMO-4 having the major contribution. The effect of reversal in orbital contributions is due to electron correlation. Therefore, its assignment


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is similar to the third ionization band and is not discussed further. Figure S7 shows the canonical molecular orbitals of conformer VI. Conformer VII

The SAC-CI calculated spectrum of conformer VII is similar to all other conformers, with conformer V being an exception. The spectrum of conformer VII was shifted to lower ionization energies and consists of six features in intensity ratio 2:1:1:1:1:1. As can be seen from Figure 2a, the first feature comprises two lowest energy ionization bands. The SAC-CI simulated spectrum of this conformer has been shifted by +0.35 to higher binding energies in order to match the calculated OVGF spectrum. In addition, the shape of the OVGF photoelectron spectrum for this conformer is very different from other conformers. The energy separation between the fifth, sixth and seventh ionization bands is small which convolutes them into a single feature in this spectrum. First ionization takes place from HOMO which is sulfur lone pair in character (see Table S7). Similar to previous assignment, the second ionization is due to HOMO-1 which is largely from oxygen lone pairs of on C=O bond of the ring A. The wavefunction of the third ionic states of conformer VII (related to the third ionization band) is a linear combination of two ionic state HF determinants related to the ionization from HOMO2 and HOMO-4 (HOMO-2 being the major contribution). NBO calculations show that HOMO-2 mostly has nitrogen lone pair character localized in ring A with some admixture of π orbital of the carbonyl group in ring A. For this ionization Koopmans’ approximation breaks down because of the electron correlation/reorganization effects. The fourth ionization band originates from HOMO-3 where HOMO-3 has nonbonding character due to lone pairs of C=O bond in ring A.



Finally, removal of electron related to the fifth ionization band is related to orbital which is a linear combination of HF single determinant related to HOMO-4 and HOMO-6 (HOMO-4 having major contribution). It is different from the assignment of the fifth ionization band in other conformers. HOMO-6 has mainly σ character is related to σ(C-S) and (C11-C12) bonds. The Koopmans’ approximation is not valid for third and fifth ionization bands in this conformer. The shapes of the canonical molecular orbitals of conformer VII are shown in Figure S8. 4. Conclusion The OVGF method predicts higher ionization energies for all conformers in comparison with the ionization energies obtained by SAC-CI method. Energy deference between SAC-CI and OVGF calculated ionization with experiment values show that OVGF calculation has more agreement with experiment (see Table 1 and Figure S9). In general, SAC-CI spectra have been shifted to higher binding energy for matching with OVGF. Based on the calculations, third and fifth ionization bands are linear combination of two HF determinate in the all conformers expect of conformer V. NBO calculations indicate that the first five valence ionizations correspond to the orbitals localized on the rings. The most important point about the photoelectron spectra of all conformers is that the removal of the electron from the σ bonding bond orbital (C-S) does not take place below 10.0 eV. The relationship between the calculated electronic structure and known biological activity can be described in qualitative terms only, but is nonetheless instructive. As the 2D diagrams (Figures 4 and 5) show the most important interactions between biotin and receptor are based on the cooperative hydrogen bonding which is unusually strong and involves ureido moiety of the imidazolidine-2-one ring33; i.e. it involves oxygen and nitrogen localized orbitals (Table 1). It is interesting to note that π+ orbital (in-phase combination of nitrogen lone pairs) and no (oxygen lone pair) change their ionization energies significantly upon


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going from the gas-phase conformations to biologically active conformations (Table 1). This conformational readjustment leads to the lowering of ionization energies (increase in orbital energies) for π+ and no. This in turn improves electron donating ability of ureido moiety which is necessary for very strong hydrogen bond formation and the tight biotin-receptor binding.

Figure 4 View of ligand-protein interactions involving biotin and streptavidin.



Figure 5 View of ligand-protein interactions involving biotin and avidin.


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Acknowledgment The authors would like to thank from the Ardakan University, Iran and Charles Sturt University, Australia for financial support.



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TOC 82x46mm (96 x 96 DPI)


Electronic Structure of Biotin Conformers Studied with SAC-CI and

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