Energetics of Radical Formation in Eumelanin Building Blocks

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Energetics of Radical Formation in Eumelanin Building Blocks: Implications for Understanding Photoprotection Mechanisms in Eumelanin Filipe Agapito, and Benedito J. Costa Cabral J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b10122 • Publication Date (Web): 29 Nov 2016 Downloaded from http://pubs.acs.org on November 30, 2016

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The Journal of Physical Chemistry

Energetics of Radical Formation in Eumelanin Building Blocks: Implications for Understanding Photoprotection Mechanisms in Eumelanin Filipe Agapito∗,† and Benedito J. Costa Cabral∗,‡ †Centro de Qu´ımica e Bioqu´ımica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal ‡Departamento de Qu´ımica e Bioqu´ımica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal E-mail: [email protected]; [email protected]

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Abstract The supramolecular structure of melanin pigments is characterised by a high concentration of radical species. Therefore, the energetics of the radical formation in melanin building blocks is key for understanding the structure and the electronic properties of the pigments at the molecular level. Nevertheless, the radical energetics of even the simplest melanin building blocks is largely unknown. In order to address this fundamental issue, the bond dissociation enthalpies (BDEs) for the melanin monomers 5,6-dihydroxy-1H -indole-2-carboxylic acid (DHICA), 1H -indole-5,6-diol (DHI), and 1H -indole-5,6-dione (IQ) were determined through high-accuracy ab initio quantum chemistry methods. Our results provide strong evidence of the importance on BDEs for explaining the experimentally observed dependence of the antioxidant properties of eumelanin pigments on the DHICA/DHI ratio, and the role that these two species play on the photoprotection mechanism.

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Introduction Melanin pigments are the quintessential supramolecular structures in human tissues. 1 Due to their broad band UV and visible absorption spectrum and strong non-radiative relaxation of photo-excited electronic states, along with their roles as anti-oxidants and free-radical scavengers, melanin pigments provide protection from photoinduced cellular damage. 2 Yet, there are conflicting reports about the role of melanin or melanin intermediates as pro-oxidants or antioxidants. 3 For instance, the presence of melanin has been reported as a requirement for the onset of UVA-induced malignant melanoma of the skin, 4 and stimulation of melanogenesis (melanin production) has been linked to an increase in UVA-induced DNA damage. 3 Melanin, more specifically neuromelanin, is also found in human brains. 5 This polymer, which is a by-product of dopamine and noradrenaline metabolism, 6,7 is posited to protect neurons from oxidative stress mediated by free metals or free radicals. 5,6,8 The depletion of dopanimergic neurons in the neuromelanin-containing substantia nigra is a telltale sign in many parkinsonian syndromes. 5,6,8–10 A deeper knowledge of the still unknown structure of the pigment, 11 starting from the eumelanin building blocks and its relative radical species, must be attained if we wish to understand the complex role played by eumelanin. One particular aspect which warrants further study is the radical chemistry of the building blocks and the energetics of radical formation. Indeed, melanin is the only biopolymer known to possess a high concentration of free radicals, both in vivo and in vitro, which can be easily detected by EPR spectroscopy. 5,12 Despite this fact, the radical energetics of melanin precursors is largely unknown. 13 A key property in the study of the radical energetics is the bond dissociation enthalpy (BDE). 14 The BDE, DH ◦ , of a given R–H bond is defined 14 as the enthalpy of reaction 1

R• + H•

R H

3


(1)


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given by equation 2,

DH ◦ (R–H) = ∆r H ◦ (1) = ∆f H ◦ (R• ) + ∆f H ◦ (H• ) − ∆f H ◦ (R–H)

(2)

where ∆f H ◦ (R• ), ∆f H ◦ (H• ), and ∆f H ◦ (R–H) are the enthalpies of formation of radical R• , of hydrogen, and of the parent molecule R–H, respectively. BDE and ∆f H ◦ data, critical to the assessment of radical energetics and reactivity, are not known for even the simplest melanin precursors. 13 In order to address this gap in our knowledge we set out to perform a theoretical study of the simplest melanin monomers. The present work is focused on the calculation of gas-phase BDEs as defined by reaction (1). In a solvent, the relative energetic stabilization of the parent molecule and the radical species is also determined by their interactions with the liquid environment. For phenol in water, an increase in the O-H BDE relative to its gas-phase value was observed. 15 Moreover, different studies pointed out the importance of protonation/deprotonation effects on BDEs. 16,17 It should be expected that these effects will also contribute to define, for some specific melanin building blocks, the values of the BDEs in aqueous phase. Major components of eumelanin, the brownish pigment present in human skin, and neuromelanin are 1H -indole-5,6-diol (DHI) and 5,6-dihydroxy-1H -indole-2-carboxylic acid (DHICA), and 1H -indole-5,6-dione (IQ) 2,12 (Fig. 1 a-c). Ab initio quantum chemistry methods were used to probe the energetics of the N–H and O–H bond dissociations in these compounds. In the absence of experimental BDEs for the eumelanin building blocks, and in order to assess the accuracy of the present adopted theoretical methods we are also reporting results for the BDEs of indole, catechol, and pyrrole (Fig. 1 d-f), for which experimental data are available. 13 Moreover, as subsequently detailed, by using appropriate chemical reactions the data for these species can be used to accurately predict BDEs for the larger eumelanin building blocks.

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2

2

HO

O

HO COOH

1

HO (a)

N H

1

HO (b)

N H

O

N H

(c)

HO NH (d)

N H

HO (e)

(f)

Figure 1: Structures of the molecules studied in the present work: (a) 1H -indole-5,6-diol (DHI), (b) 5,6-dihydroxy-1H -indole-2-carboxylic acid (DHICA), (c) 1H -indole-5,6-dione (IQ) (d) indole, (e) catechol, (f) pyrrole. Note the indexing used to refer to the O–H bonds of DHI and DHICA.

Computational Methods The structures of all the species were optimized with the B3LYP-D3 functional, 18–20 using the cc-pVTZ basis set (dubbed VTZ). 21 The -D3 suffix denotes the addition of the DFT-D3 18 dispersion correction to the B3LYP hybrid density functional. 19,20 Zero-point vibrational energy (ZPVE) and thermal enthalpy corrections at T = 298.15 K for each molecule were determined from harmonic vibrational frequencies calculated at the B3LYP-D3/VTZ level. All thermochemical data herein presented reports to this temperature. Frequencies were scaled by 0.9889. 22 These optimized structures and corrections were used in all subsequent calculations. The gas-phase standard enthalpies of formation at 298.15 K (∆f H ◦ ) of catechol, the catechol radical, pyrrole, and the pyrrolyl radical were determined using the W1-F12 composite procedure. 23 This procedure relies on explicitly correlated coupled-cluster calculations 24 and a judicious choice of basis set extrapolation techniques in order to reach the all-electron relativistic CCSD(T) complete basis set limit. As reported by the proponents of this method, for molecules containing only first-row elements W1-F12 reaches sub-kcal/mol accuracy. 23 Additionally, the energies of 5,6-dihydroxy-1H -indole-2-carboxylic acid, 1H -indole-5,6diol, 1H -indole-5,6-dione, catechol, pyrrole, indole, and their nitrogen- and oxygen-centered

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radicals were also obtained form explicitly correlated CCSD(T)-F12a calculations 24 using the 3C(Fix) ansatz 24,25 and the cc-pVDZ-F12 26 orbital basis set (dubbed VDZ-F12). An exponent β = 0.9 was used for the Slater-type frozen geminal. 27 Resolutions of the identity (RI) were performed using the cc-pVDZ-F12/OptRI basis set 28 within the complementary auxiliary basis set (CABS) approach. 29 The cc-pVDZ/JKFIT basis set 30 was used in the density fitting (DF) of Fock and exchange matrices, and the aug-cc-pVDZ/MP2FIT basis set 31 was used in DF of the remaining integral quantities. The CABS singles correction, in which HF orbitals are allowed to relax in the CABS space, 24 was added for all explicitly correlated data reported. The enthalpies for each of the species under study were determined by adding the thermal corrections for T = 298.15 K obtained from the B3LYP-D3/VTZ calculations to the CCSD(T)-F12/VDZ-F12 energies. The diagonal Born-Oppenheimer corrections (DBOC), 32–34 which are required for the W1-F12 protocol were computed with the CFOUR program. 35 All other calculations were performed using the Molpro 2012.1 quantum chemistry package. 36

Results and Discussion The W1-F12 calculations resulted in gas-phase standard enthalpies of formation of −266.7 kJ·mol−1 , −150.3 kJ·mol−1 , 108.9 kJ·mol−1 , and 291.4 kJ·mol−1 , repectively for cathecol, cathecol radical, pyrrole, and pyrrolyl radical (Table 1). These ∆f H ◦ data were determined from the W1-F12 enthalpy of atomization at 298.15, ∆at H ◦ , of each compound ◦ ◦ using ∆f H298 (H) = 217.998 ± 0.000 kJ·mol−1 , ∆f H298 (C) = 716.873 ± 0.057 kJ·mol−1 , ◦ ◦ ∆f H298 (O) = 249.229 ± 0.002 kJ·mol−1 , and ∆f H298 (N) = 472.435 ± 0.024 kJ·mol−1 . 37 The

contributions of the components of the W1-F12 protocol for the enthalpies of atomization of each compound are listed in Table 1. We have recently reviewed the thermochemistry of dihydroxybenzenes, 38 where the gas-

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Table 1: Components of the gas-phase standard enthalpies of atomization used to calculate the gas-phase standard enthalpies of formation from W1-F12 calculations.a component

catechol 4817.5 1598.6 151.5 30.7 2.1 −6.5 −4.0 0.1 −215.6

catechol radical 4506.9 1546.1 155.1 29.5 2.1 −6.0 −4.0 −0.2 −189.4

SCF val. CCSD val. (T) core CCSD core (T) relativity spin-orbit DBOCb Hthermal c ∆at H ◦ 298K d ∆f H ◦ 298K e

pyrrole 3272.9 1099.4 95.4 21.8 1.4 −4.0 −1.4 0.2 −164.6

pyrrolyl radical 2927.3 1017.6 93.7 19.4 1.4 −3.5 −1.4 −0.9 −133.1

6374.3 −266.7

6040.0 −150.3

4321.0 108.9

3920.5 291.4

a

All data in kJ·mol−1 at T = 298.15 K. b Diagonal Born-Oppenheimer correction. c Thermal enthalpy correction at 298.15 K. d Enthalpy of atomization at 298.15 K. e Enthalpy of formation at 298.15 K. Computed using ∆f H ◦ 298 K for atoms from Ref. 37 (see text).

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phase enthalpy of formation of catechol was also determined with W1-F12. Therein a slightly lower value of −270.6 kJ·mol−1 was obtained for this ∆f H ◦ . The ca. 4 kJ·mol−1 difference between these two enthalpies of formation can be ascribed to: (i) the use of different vibration scale factor for thermal corrections — previously a value of 0.985, prescribed with W1-F12, 23 was used, whereas the current calculations relied on a more recent value of 0.9889; 22 (ii) the slight differences in integration grids and in the definition of B3LYP for NWChem, 39 used in the previous work, and Molpro, used for the present calculations — in particular, NWChem uses VWN1 with RPA parameters 40 as local correlation functional, whereas Molpro uses VWN5; 40 and (iii) the use of a different spin-orbit splitting for oxygen — previously a splitting of −0.00235 eV from ref. 41 was used, whereas the present calculations were performed using a value of −0.00966 eV, calculated from the atomic spectroscopic data tabulated by Sansonetti. 42 The W1-F12 enthalpies of formation, together with the CCSD(T)-F12 enthalpy data, were used to calculate the O–H and/or N–H bond dissociation enthalpies for the species under study. The data obtained from W1-F12 calculations afforded benchmark quality N–H and O–H BDEs for catechol and pyrrole, which were used as anchors for the reactions required to obtain BDEs of the larger species. Using the reaction enthalpies for reactions 3 and 4, the BDEs of interest, DH ◦ (R–H), were determined from equations 5 and 6. HO

HO

R H +

R •

•

+

O

R H +

(3) HO

R• +

NH

(4)

DH ◦ (R–H) = ∆r H ◦ (3) + DH ◦ (C6 H5 O2 –H)

(5)

DH ◦ (R–H) = ∆r H ◦ (4) + DH ◦ (C4 H4 N–H)

(6)

N•

Here DH ◦ (C6 H5 O2 –H) and DH ◦ (C4 H4 N–H) are, respectively, the catechol O–H and the

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pyrrole N–H BDEs. The BDEs calculated by each of these routes is listed in Table 2 together with the available experimental data. 13 Table 2: Bond dissociation enthalpies (BDEs in kJ·mol−1 ) determined in the present work for the molecules under study, together with the available experimental data. Selected values in bold.a CCSD(T)-F12 Ic IId IIIe 332.7 335.6 397.5 399.3 386.1 387.8 389.0 342.5 344.2 345.4

molecule

BDE

W1-F12b

catechol pyrrole indole IQg

O–H N–H N–H N–H

334.4 400.5

DHIh

N–H O–1 Hi O–2 Hj

377.5 315.2 319.3

379.2 317.0 321.0

380.5 318.2 322.2

DHICAk

N–H O–1 Hi O–2 Hj COO–H

401.3 325.8 324.7 465.1

403.0 327.5 326.4 466.9

404.3 328.7 327.6 468.1

exptlf 339.6; 342.3; 344.7 405.8; 405.8±8.4; 387.6±4.8; 393.0±0.5 380; 393.7

a

All data in kJ·mol−1 at T = 298.15 K. b Determined from the enthalpies of formation in table 1 and ∆f H ◦ (H) = 217.998 ± 0.000 kJ·mol−1 from ref. 37. c Determined from homolysis reaction, eq. 1. d Determined from the reaction with catechol, eq. 3. e Determined from the reaction with pyrrole, eq. 4. f All experimental data extracted from Ref. 13. g 1H -indole-5,6-dione. h 1H -indole-5,6-diol. i O–H bond located on the same side of N–H bond (see fig. 1). j O–H bond located on the opposite site of the N–H bond (see fig. 1). k 5,6-dihydroxy-1H -indole-2-carboxylic acid.

Analysis of the data in table 2 reveals an excellent agreement between experimental and W1-F12 BDEs. In addition, comparison of the BDEs obtained for catechol and pyrrole using CCSD(T)-F12 with the corresponding W1-F12 values, shows these two methods yielded data with equivalent accuracy. This is particularly true if reactions 3 and 4 are used, since then the deviations between CCSD(T)-F12 and W1-F12 values amount only to ca. 1 kJ·mol−1 . Due to error cancellation, enthalpy data obtained from chemical reactions is more accurate when there is conservation of the chemical environments on the left- and right-hand sides of the chemical equation used. 43 Consequently, the more accurate O–H and N–H BDEs are 9



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obtained from reaction 3 and reaction 4, respectively. It should be, nevertheless, stressed that both reactions yield very similar results for all BDEs studied. Moreover, even using an homolysis reaction with CCSD(T)-F12 leads to similar data, which is indeed a testament to the accuracy of this method. Armed with accurate BDE data we can now proceed to discuss their trends. The O– H BDEs in the catechol moiety of DHI are ca. 15 kJ·mol−1 lower than that of catechol, 334 kJ·mol−1 . This should be related with the increased delocalization afforded by the addition of the pyrrole moiety. The electronic delocalization seems to be related to the average C-C bond distance (). In catechol is 1.390 ± 0.005 ˚ A, and it is increased to 1.396 ± 0.150 ˚ A in the catechol moiety of DHI. The same tendency is observed when comparison is made between the radical species: is 1.409 ± 0.034 ˚ A in the catechol radical, and 1.415 ± 0.037 ˚ A in the catechol radical moiety of the DHI radical. A similar energetic stabilization due to electronic delocalization effects should be expected in the case of of 5,6-dihydroxy-1H -indole-2-carboxylic acid, yet to a smaller extent, given that these O–H BDEs in DHICA amount to ca. 327 kJ·mol−1 . The highest BDE in the set of compounds studied is that of the O–H bond the carboxyl group of DHICA, viz. 467 kJ·mol−1 . The N–H BDE in the pyrrole moiety is highly sensitive to the substituents of the fused ring system, ranging from 404 kJ·mol−1 in 5,6-dihydroxy-1H -indole-2-carboxylic acid to 345 kJ·mol−1 in 1H -indole-5,6-dione. In comparison with the other species, the lowest O–H BDEs of DHI (317 and 321 kJ·mol−1 ) and DHICA (326.4 and 327.5 kJ·mol−1 ) are in keeping with the well characterised presence of semiquinones in pulse radiolysis investigations of the oxidation of indolic melanin precursors. 44 However, O–H BDEs in DHICA are 5–10 kJ·mol−1 higher than those of DHI, strongly suggesting that the formation of radicals from these species and the role they may play as radical scavengers is significantly different. 45 Further insight can be gained by analysing the kinetic differences in the O–H abstraction from DHICA and DHI. In general, the rate constant for a chemical process, k, at a given

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temperature, T , is related to its activation energy, Ea , by the Arrhenius equation: 46

Ea k = A exp − RT

(7)

Here, A is an empirical pre-exponential factor, and R is the perfect gas constant. 46,47 For a barrierless process the activation energy is equivalent to the reaction enthalpy, ∆r H ◦ . In particular, this implies that for the homolytic dissociation of a given R–H bond Ea ≡ DH ◦ (R–H). 48 Hence, assuming a common pre-exponential factor for DHICA and DHI, the ratio between their rate constants can be assessed with equation 8. kDHI kDHICA

= exp

DH ◦DHICA − DH ◦DHI RT

(8)

Using the bond dissociation enthalpies, DH ◦ , listed in table 2 in equation 8 we estimate that, for similar concentrations of DHICA and DHI, kDHI /kDHICA for the O−H homolytic dissociation is in the [9 – 76] range. Experimental information on the generation of radical species from DHI and DHICA indicates that DHI-melanin acts as a prooxidant, and generates a much larger amount of reactive oxygen species (ROS) than DHICA-melanin in the same range of concentrations. 45 Furthermore, there is some evidence that the DHICA/DHI ratio in the melanin polymer backbone may influence UV absorption as well as the antioxidant property of eumelanin. 49 Peles et al. 50 have reported that an increase of the DHICA/DHI ratio in eumelanin is linked with a larger UV absorption coefficient in melanosomes. Moreover, the decrease of the DHICA/DHI ratio with age in bovine eye melanin possibly explains the decreased absorption of UV as well as the ROS scavenging insufficiency of eumelanin with ageing. 49 The experimental information points out the fact that the DHICA/DHI ratio plays a fundamental role in the photoprotective properties of the eumelanin pigments. Our results can be useful for understanding how this ratio is influenced by the difference in BDEs and relative rate constants for DHICA and DHI. 11



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Conclusions In the present work the energetics of 5,6-dihydroxy-1H -indole-2-carboxylic acid and 1H -indole-5,6-diol, the two main constituents of eumelanin, were studied using high-level quantum chemistry methods, namely W1-F12 and CCSD(T)-F12. These methods, which rely on an explicit treatment of correlation, were shown to yield accurate bond dissociation enthalpies (BDEs). Analysis of these data revealed that the DHICA O–H BDE is ca. 5 to 10 kJ·mol−1 higher than that in DHI. This, in turn, implies that the rate constant for O–H abstraction in DHI is at least an order of magnitude larger than in DHICA. It is expected that the present results for the O–H BDEs can be useful for explaining the experimental evidence indicating that, in the same range of concentrations the prooxidant effect and reactive oxygen species generation by DHI-melanin is superior to that of DHICAmelanin. However, further investigations on the energetics of the O-H bond dissociation in small aggregates of DHI/DHICA or in condensed phase can be extremely important for a better understanding on the relationship between the theoretically predicted BDEs and the experimental information. The present work highlights the fact that the accurate prediction of thermochemical data for eumelanin building blocks is of paramount importance for a better understanding of the different roles DHICA and DHI play in the photoprotection mechanism of eumelanin pigments. Supporting information Cartesian coordinates for the optimized geometries of the relevant species in xyz format. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgement This work was supported by Funda¸caõ para a Ciência e a Tecnologia (FCT), Portugal (UID/ MULTI/00612/2013). F. A. thanks FCT for a post-doctoral grant (SFRH/BPD/74195/ 2010). 12


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References (1) Prota, G. Melanins and Melanogenesis; Academic Press, 2012. (2) Meredith, P.; Sarna, T. The Physical and Chemical Properties of Eumelanin. Pigment Cell Res. 2006, 19, 572–594. (3) Denat, L.; Kadekaro, A. L.; Marrot, L.; Leachman, S. A.; Abdel-Malek, Z. A. Melanocytes as Instigators and Victims of Oxidative Stress. J. Invest. Dermatol. 2014, 134, 1512– 1518. (4) Noonan, F. P.; Zaidi, M. R.; Wolnicka-Glubisz, A.; Anver, M. R.; Bahn, J.; Wielgus, A.; Cadet, J.; Douki, T.; Mouret, S.; Tucker, M. A. et al. Melanoma Induction by Ultraviolet A but not Ultraviolet B Radiation Requires Melanin Pigment. Nat. Commun. 2012, 3, 884. (5) Zucca, F. A.; Basso, E.; Cupaioli, F. A.; Ferrari, E.; Sulzer, D.; Casella, L.; Zecca, L. Neuromelanin of the Human Substantia Nigra: An Update. Neurotox. Res. 2013, 25, 13–23. (6) Segura-Aguilar, J.; Paris, I.; Mu˜ noz, P.; Ferrari, E.; Zecca, L.; Zucca, F. A. Protective and toxic roles of dopamine in Parkinson’s disease. J. Neurochem. 2014, 129, 898–915. (7) Wakamatsu, K.; Tabuchi, K.; Ojika, M.; Zucca, F. A.; Zecca, L.; Ito, S. Norepinephrine and its Metabolites are Involved in the Synthesis of Neuromelanin Derived from the Locus Coeruleus. J. Neurochem. 2015, 135, 768–776. (8) Fedorow, H.; Tribl, F.; Halliday, G.; Gerlach, M.; Riederer, P.; Double, K. Neuromelanin in Human Dopamine Neurons: Comparison with Peripheral Melanins and Relevance to Parkinson’s Disease. Prog. Neurobiol. 2005, 75, 109–124. (9) Reimão, S.; Pita Lobo, P.; Neutel, D.; Correia Guedes, L.; Coelho, M.; Rosa, M. M.; Ferreira, J.; Abreu, D.; Gon¸calves, N.; Morgado, C. et al. Substantia Nigra Neuromelanin 13



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