Calculation of Standard Reduction Potentials of Amino Acid Radicals

Article Cite This: J. Phys. Chem. A XXXX, XXX, XXX−XXX

pubs.acs.org/JPCA

Calculation of Standard Reduction Potentials of Amino Acid Radicals and the Effects of Water and Incorporation into Peptides David M. Close* Department of Physics, East Tennessee State University, Johnson City, Tennessee 37614, United States

Peter Wardman† Gray Cancer Institute, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, U.K. ABSTRACT: Guanine (Guo) is generally accepted as the most easily oxidized DNA base when cells are subjected to ionizing radiation; calculations of the standard reduction potential of the guanyl radical, Eo(Guo•+/Guo) are within ∼0.1 V of experimental values in aqueous solution extrapolated to standard conditions. While a number of experimental studies have shown some amino acid radicals have redox properties at pH 7 which suggest or confirm a capacity for radical “repair” by electron transfer from the amino acid to Guo•+ (or its deprotonated conjugate), the redox properties of the radicals of other amino acids, including methionine, lysine and cystine, are less well characterized. In addition, the effects of incorporation of the amino acids into peptides, or the effects of water of hydration on calculated potentials, have not been extensively studied. In this work, calculations of standard reduction potentials of radicals from model amino acids as they appear in histone proteins are performed. To predict redox properties at pH 7, acid dissociation constants (pKas) of both radical and ground state amino acids are required. In some instances these are not experimentally determined and calculated pKas have been derived for some common amino acids and compared with experimental values.

■

Calculations the standard reduction potential Eo of radical/ reductant couples are combined with the acid dissociation constants (pKa, abbreviated to pK below) of both radical (oxidant, pK0) and reductant, pKr) when appropriate, to calculate the midpoint reduction potentials Em7 of the couples at pH 7 using well-known equations.6 Calculated standard reduction potentials of radicals from N-methyl substituted DNA bases reported by Pscuik et al.2 agree fairly well with experimental data, although as Schroeder et al.7 have noted (and discussed in our recent paper3) care must be taken to distinguish between e.g. values for the couples Eo(Nuc•,H+/ NucH+) and Eo(Nuc•+/Nuc). Until recently calculated acid−base dissociation constants were not in good agreement with experimental data. SadlejSosnowska computed the pKs of nine model compounds and studied the influence of factors including the SCRF model applied, choice of thermodynamic cycle, atomic radii used to build a solvent, optimization of geometries, inclusion of electron correlation, and the dimension of the basis sets8 including ca. 60 pages of supporting information. Calculations of the pK for phenol for example have been in the range of 18− 20 compared to the experimental value of 10.0. We have

INTRODUCTION The methods developed by Schlegel and co-workers to calculate standard reduction potentials of DNA base radicals or their N-methyl analogues have proven valuable.1,2 We recently explored and extended such methods to include calculations of prototropic equilibria and the effects of uncertainties in these parameters in extrapolating estimates of redox properties of DNA base radicals to pH 7.3 At pH 7, the midpoint reduction potential (Em7) for the neutral guanosine radical is of the order of 0.2−0.3 V higher than those of the radicals of e.g. tyrosine, tryptophan and histidine, so that radical “repair” (or at least, a thermodynamically favorable reaction) involving these amino acids is feasible; indeed, Milligan et al. demonstrated a reduction by such amino acids of DNA damage following exposure of double-stranded DNA plasmids to radiolysis-generated thiocyanate radicals.4,5 (The latter radicals are only significantly reactive toward guanosine residues.) This concept of DNA damage and repair may model part of the interaction of radiation damage to DNA with histone proteins, and it merits further study. However, not all amino acids of interest have well-characterized redox properties. We have now tested these computational methods with amino acids having known reduction potentials, extending estimates of redox properties to previously poorly characterized amino acids, and explored the effects on models both of peptide bond formation and of water of hydration. © XXXX American Chemical Society

Received: October 31, 2017 Revised: December 7, 2017 Published: December 8, 2017 A

DOI: 10.1021/acs.jpca.7b10766 J. Phys. Chem. A XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry A

using the default parameters give pK = −3.9. Changing the cavity scaling factor α from 1.0 to 0.98 yields agreement between calculation and theory. Calculations of Prototropic Properties of Imidazole, Indole, and Aniline and Their Radicals. Imidazole (ImH) has an experimental pK = 7.0 for deprotonation of the cation ImH2+. Psciuk et al. recommend a cavity scaling factor α = 1.0.2 Our calculation using α = 1.0 yields a pK = 6.2, fairly close to the experimental value. For the imidazole radical-cation the experimental pK = 6.1,14 while our calculated value is 5.85 (using only the SMD default parameters). The experimental pK of indole is 21.0 (in dimethyl sulfoxide).15 Calculations using the default parameters give a pK = 21.95 and with an α = 0.95 the computed pK = 21.2. The indolyl radical-cation has an experimental pK = 4.6−4.9.16,17 Our calculations using the default parameters give a pK = 5.3 quite close to the experimental value. The pK of the amino moiety can vary widely (e.g.: ammonia = 9.26; aniline = 4.58).18 Using the methods outlined here, our calculated pK of aniline is 5.1, fairly close to the experimental value. The radical-cation of aniline has pK = 6.4.19 Calculations by Yu et al. on this species, with the IEFPCM model to compute the solvation free energy, yield a value 5.5 units lower than the experimental value.20 Our calculations with the SMD solvation model yields pK of 6.1, in good agreement with the experimental value. These results show that the methods employed can give good results for models involving amino moieties at least for an aromatic amine. Calculations of Prototropic Properties of Thiols. Sadlej-Sosnowska computed the pK of thiophenol as 12.0 compared to the experimental pK of 6.6 for deprotonation of the thiol.8 Our calculations with the default α = 1.0 gives a pK of 13.8; using the suggested α = 0.90 for anions reduces this to 11.1. In some cases one can improve these calculations with microhydration. Putting a single water molecule just beyond the − SH bond in thiophenol improved these calculations such that with α = 0.90 the calculated pK = 7.4. Thapa and Schlegel report calculations on the pKs of thiols; their calculation of thiophenol with three water molecules gave a pK close to the experimental value.21 The crystal structure of cysteine shows a single H-bond to the −SH group.22 For the model CH3CH2SH, our basic calculations indicate pK = 20.1 but incorporating a hydrogen bond to a single water molecule reduces this to 16.2, further lowered to 12.96 with α = 0.90. (While generally, changing the cavity scaling factor lowers the calculated pK by only 1.0−1.5 units, this is clearly not the case for the amino acid side chains that contain sulfur, where larger reductions are found.) For the model CH3CH2SH···H2O the radical-cation has a calculated pK = −10.7. Calculations of the Standard Reduction Potentials of the Amino Acids in Proteins. Phenol, indole, and imidazole were used as model oxidizable moieties in aromatic amino acids (Table 1), adding a methyl group to model the incorporation of the amino acids as they appear in a histone protein. Thus, the first two entries in Table 1 are phenol and 4-methylphenol, the latter representing the tyrosyl moiety in peptides; tryptophan is modeled as 3-methylindole. Table 1 shows that the effect of the methyl group is to lower the reduction potential of the radicals, e.g. the calculated standard reduction potential for the phenoxyl radical is 1.08 V (cf. experiment, ∼1.35 V),23,24 lowered to 0.87 V in 4-methylphenol. For the indolyl radical-cation the

explored approaches to improving the calculations of pKs since these are not always available (especially for the radicals).

■

COMPUTATIONAL METHODS Calculations to be performed will follow the methods developed by Schlegel and co-workers on the N-methyl substituted DNA bases.1,2 Briefly, (i) the geometry of the dominant tautomer was optimized at the B3LYP/6-31+G(d,p) level of theory and frequencies were calculated. (ii) The gas phase single-point calculation was conducted on the gas phase optimized geometry at the B3LYP/aug-cc-pVTZ level of theory; and (iii) The geometry of each tautomer was optimized in aqueous solution at the SMD/B3LYP/6-31+G(d,p) level of theory9 using the Gaussian 09 suite of programs.10 The nature of the stationary points obtained was checked by calculating the analytic Hessians to ensure the absence of imaginary frequencies, indicating at least local minima had been reached. Details for calculating the midpoint reduction potential Em7 are as follows. The standard reduction potentials Eo were calculated using the methods reported by Pscuik et al.2 The acid dissociation constants were calculated and used in the equations given by Wardman6 to determine the midpoint reduction potentials Em7. The study by Sadlej-Sosnowska8 showed that it is not easy to calculate the acid dissociation constants. For some of the SMD calculations in the present study, small adjustments in the cavity scaling factor α were made. Further improvements in these calculations were obtained by using one or two water molecules to simulate the hydrogen bonds from waters of hydration or neighboring molecules make to the solute (as discussed below).

■

RESULTS AND DISCUSSIONS Calculations of Prototropic Properties of Phenol and its Radical Cation. As noted above calculations of the pK of phenol by Sadlej-Sosnowska gave values of 18−20 compared to the experimental value (pK = 10.0).8 Using the three steps described above with the solvation energy computed with SMD calculates the same pK as ca. 15.0. Changing the cavity scaling factor usually lowers the pK by only 1.0−1.5 units, so one must look for other solutions. The problem here is that solvation models do not include any H-bonds to the solute. The crystal structure of L-tyrosine shows two H-bonds to the phenol OH.11 We therefore simulated these H-bonds by two water molecules (Figure 1).

Figure 1. Calculated geometries of phenol (left) and phenolate anion (right) with two water molecules.

With the solvation energy of the phenolate anion computed with SMD the pK is now 10.3 in good agreement with experiment. A recent study by Ghosh et al. has shown similar favorable results on phenol using 1−4 water molecules.12 One electron oxidation of phenol produces the phenol radical-cation with an experimental pK = −2.13 Calculations B


Article


in Table 2 produce an Eo = 0.67 V and in common with the other results in Table 2 at the level of theory used herein are slightly below the experimental results. The model used for the lysine side chain was CH3(CH2)3NH3+, for which the calculated Eo = 1.67 V. The experimental value, for comparison, is not for this model but is calculated from the value Em7 = 1.5 V determined by Armstrong et al.35 for the glycine zwitterion (O2CCH2NH3+). The thiol tripeptide glutathione has a cysteine residue and one expects the Eo of the glutathione thiyl radical to be similar to that from cysteine. While experimental values of the reduction potential of the couples E(RS•,H+/RSH) are available at pH ∼ 7,33 extrapolation to calculate standard potentials are somewhat uncertain because the pK values for dissociation of the −CO2H moieties may differ in reductant and oxidant (radical). However, a standard potential of the order of 1.35 V is likely for the couple Eo(RS•,H+/RSH).33 It is important here to know if more realistic models of a peptide further change the reduction potential, such as the peptide backbone including tyrosine shown in Figure 2. The

Table 1. Calculated and Experimental Standard Reduction Potentials model phenol 4-Me-phenol indole 3-Me-indole imidazole 4-Me-imidazole CH3−CH2−SH···H2O CH3-2(CH2)-S-CH3 CH3−S-S-CH3 ascorbate CH3-(CH2)3-NH3+ glutathione 9-MeGuanine

Eo calcd (V) 1.08 0.87 1.09 0.85 1.52 1.31 1.20 1.43 1.39 0.67 1.67 1.15 1.37

a

Eo exptl (V) 1.38b 0.97b 1.24c 1.24b 1.77d (1.58)e 1.33f ∼1.66g 1.70h 0.99i 1.91j unknownk 1.58l

a

Psciuk et al.2 bStanbury et al.28 cMeréni et al.29 dPekmez et al.30 Computed from E7. fSurdhar and Armstrong.24 gFrom DMS.27 h Ahmad et al.31 iSteenken et al.32 jComputed from E7. kMadej et al.33 l Steenken and Jovanovic.34 e

calculated standard reduction potential is 1.09 V, dropping to 0.85 V with the 3-methyl substituent (to model tryptophan). The calculated standard potential is 1.52 V for imidazole, reduced to 1.31 V in 4-methylimidazole (the model for histidine). Table 1 includes our calculations of the standard reduction potentials of some sulfur-containing amino acids. The value for CH3CH2SH (the model for cysteine) with one water molecule is 1.20 V. There are no reliable experimental data on the oneelectron reduction potential of the methionine radical-cation.25 The affinity of sulfur for the electrode metal evidently leads to voltammograms that are not reversible.26 Calculations on our model for methionine give an Eo = 1.43 V. Therefore, one expects the experimental Eo for both dimethyl sulfide and methionine to be about 1.6−1.7 V (as shown in Table 1).27 There is considerable interest in the antioxidant properties of ascorbic acid. Ascorbic acid has two ionizable hydroxyl groups with pK1 = 4.2 and pK2 = 11.6, thus the ascorbate monoanion is the dominate form at physiological pH. The calculations shown

Figure 2. Side chain of tyrosine in a peptide, with the peptide ends terminated by methyl groups.

Table 2. Calculated Values of Standard Potentials and pKs and Comparison with Experimental Values (in Parentheses) model

Eo calcd (V)

pKr

tyrosyl:2H2O

1.08

9.48 (10.1)a

tryptophanyl

0.85

22.7 (20.95)d

histidinyl cysteinyl:H2O (1)

1.31 1.20

cysteinyl:H2O (2)

1.38

methioninyl cystinyl lysinyl ascorbate

1.43 1.39 1.65 0.78

glutathione:H2O 9-MeGuanine

1.16 1.37p

6.27 (6.0)f 16.24 (10.6)h 12.96 [α = 0.90] 14.67 (8.33)j 8.51 [α = 0.90] 51.3 33.6 11.42 (11.1)m 4.16 (4.2)n 11.11 (11.5)n 8.53 3.20p

pKo −3.72 (−2.0)b −1.60 [α = 0.95] 6.16 (4.2)e 4.42 [α = 1.04] 5.24 (5.2)f −16.66 −10.68 [α = 0.90] −10.08 −5.45[α = 0.95] −3.93 (−2.0)k 2.79 3.45 −1.72 (−0.45)n −0.45 [α = 1.03] −6.07 3.34p

Em7 calcd (V) 0.87 (0.91)c 0.68 (1.03)c 0.90 (1.17)g 0.79 (0.93)i 0.97 1.01 (1.2−1.5)l 0.98 (1.1)l 1.24 0.34 (0.30)n 0.75 (0.92)o 0.96p (1.29)q

a

Lide,41 bDixon et al.,13 cStanbury,28 dBordwell et al.15 eSolar et al.42 fRao et al.14 gNavaratnam et al.43 hIrving et al.37 iRauk et al.44 jDawson et al.38 Huang et al.45 lAhmad et al.31 mForsyth et al.46 nSteenken et al.32 oMadej et al.33 pPsciuk et al.2 and Steenken and Jovanovic34

k

C


Article


radical cation MetS•+ of methionine. MetS•+ can deprotonate at the methyl group (pK=-6)39 or at the adjacent methylene (pK=-2).40 The present calculations were on the adjacent methylene deprotonation. For this choice, the model calculated Em7 = 1.01 V as shown in Table 2. Cystine involves the dimerization of two cysteine side chains. From the values calculated in Table 2 cystine seems to have parameters in common with methionine. The calculated Em7 = 0.98 V is closed to the Em7 of methionine. To test the span of computed Em7 it is important to consider a peptide side chain that has a midpoint reduction potential Em7 greater than that of the guanine cation such as lysine. The model for the side chain of lysine was CH3−CH2−CH2−NH3+. The computed value of pK was 11.42, which is closed to the experimental value of 11.1. There is no known value of the experimental value of pKox for lysine. Our calculated value was 3.45. Using these two pKs and the computed the Eo = 1.65 V from Table 1, the Em7 was calculated to be 1.24 V as shown in Table 2. To complete Table 2 two important antioxidants were considered. The first entry is ascorbate. The calculated value for Eo was taken from Table 1. The calculated values for pKr1, pKr2, and pKo1 in Table 2 are all seen to be remarkably close to the experimental values. Because this agreement is so good, the computed value of Em7 = 0.34 agrees with the experimental value of Em7. Finally calculations are shown for the tripeptide glutathione. Since the central portion of glutathione is cysteine, it is useful to have the S−H hydrogen bonded to a single H2O. The calculated value of pKr = 8.53 for glutathione is close to the same value for cysteinyl:H2O (2). There is no experimental value of the pK0 for glutathione. The computed value Em7 = 0.75 is slightly below the experimental value of 0.92 reported by Madej and Wardman.33 This compares with the calculated E m7 = 0.79 for cysteinyl:H2O. This is interesting and one can see that while the calculations on cysteinyl: H2O (2) and glutathione are comparable, this would not be the case for a calculation on just the amino acid cysteine. In the literature one sees that calculations on cysteine invariably involve intramolecular Hbonds between −S−H···O−H moieties (in the gas phase) and between NH3···O−C moieties (in the zwitterion). For the tyrosine, tryptophan, histidine, and ascorbate entries there are reliable experimental values of pKr and pK0, so it is easy to make slight adjustments in the cavity scaling factor to come close to the experimental values. For the other entries, there are missing experimental results, so no further refinements were attempted. This completes the second portion of the present study.

calculations presented here involve the energy of removing an electron (ionization energy) along with the solvation energy of the oxidized species. This presents a problem for the amino acid calculations since they are neutral molecules in the gas phase and zwitterions in the solution phase. This problem can be circumvented by using models based on just the side chains of the amino acids (as they appear in a histone protein). The computed Eo = 1.12 V for the model shown in Figure 2 is close to the Eo value (1.08 V) shown in Table 1 for tyrosine. Highlevel calculations with ca. 20 heavy atoms are time-consuming, and the comparison of the model with only the additional methyl group suggests such complex models are not essential. Overall, comparing calculated and experimental standard reduction potentials in Table 1 shows the calculated values at the level of theory used above are consistently below experimental values. Fu et al.36 calculated ionization potentials at the B3LYP level of theory and found they also underestimated the experimental data on average by 0.28 eV.

■

CALCULATING THE REDUCTION POTENTIALS OF THE AMINO ACIDS IN PROTEINS The first entry in Table 2 has the calculations for the tyrosine residue. From the discussion above it was shown that best results were with the inclusion of two water molecules in calculations (as shown in Figure 1). So the model presented here is the tyrosine side chain terminated by a methyl group. The experimental pKs are known. The calculated pKr is close to the experimental value, while the pK0 is calculated to be close to the experimental value if the cavity scaling factor α = 0.95 is used. The calculated Em7 = 0.87 V is close to the literature value of 0.91 V.28 For the tryptophan side chain the model used is the indole ring terminated by a methyl group. Again the experimental pKs are known and one sees that the calculated pKs are close to the experimental results with only a small change in the cavity scaling factor for the radical cation. The calculated Em7 = 0.68 V is below the experimental value of 1.03 V. The model for the histidine side chain is 4-Me-imidazole. One sees that the calculated pKs are remarkable similar to the two experimental pKs. The calculated Em7 = 0.90 V is below the experimental value of 1.17 V. The next entry in Table 2 is for cysteine. In the discussion above a single H2O near the S−H group was used to improve the fit between calculated and experimental results. So then the first model for the cysteine side chain was CH3−CH2−S−H··· H2O. For this model there is an experimental pKr = 10.6 in the literature.37 The first try on calculating this was 16.24 V, which dropped to 12.96 with α=.90. There are no experimental pKox for cysteine, so no refinements were attempted for the value calculated in Table 2. One problem here with cysteine is the pKr = 10.6 experimentally determined for the ethanethiol model above.37 There is an experimental pKr = 8.33 for L-cysteine.38 Of course the pKs can change with environment and there is a possibility that the amino acid backbone H3N+-CH−COO− makes a difference. So calculations were performed on L-cysteine:H2O (model 2 in Table 2). One sees different outcomes for these two calculations: Em7 = 0.79 for cysteine:H2O (1) and Em7 = 0.97 for cysteine:H2O (2). The next entry in Table 2 is methionine, for which there is not much experimental data. Calculations on CH3-2(CH2)-SCH3 in Table 2 have Eo is 1.43 V. Our calculated value of pKr = 51.3. There are also reports of experimental results on the

■

IS THERE SUFFICIENT ACCURACY IN CURRENT REDOX POTENTIAL CALCULATIONS TO PREDICT WHICH AMINO ACIDS WILL REDUCE A DNA BASE LESION? The next step is to compare the computed results on Em7 tabulated in Table 2 with the calculated value of the midpoint reduction potential at pH 7 for the neutral guanosine radical listed as 0.96 V in Table 2. Note that this is being modeled as 1MeGuanine. So one needs to find the midpoint potentials that are below that of 1-MeGuanine. Using the computed values in Table 2 being tyrosyl (0.87 V), tryptophanyl (0.68 V), histidinyl (0.90 V), and cysteine (1) (0.79 V). To summarize D


Article


molecules.21 There best results were obtained using three water molecules around the S−H moiety, with no need to modify the cavity scaling factor in the SMD calculations. Our approach was to use only one or two water molecules in positions obtained from the hydrogen bonding schemes in single crystal X-ray structures, followed by small changes in the default cavity scaling factor. It is pleasing to note that both procedures produced rather good results. Some of the calculations presented herein show better agreement with experimental results with the addition of one or two water molecules. It is important therefore to see how much water is present in nucleosomes. In one study a nucleosome core particle containing a 147 base-pair sequence has been characterized from an X-ray crystal at 1.9 Å resolution.52 In that study, more than 3000 water molecules were identified. For a particular tyrosine residue, the arrangement of the water molecules around the −OH moiety looked like the arrangement shown in Figure 1. The study also shows numerous water bridges between protein and DNA. In most cases considered here, there is good agreement between the calculated pKs and the known experimental values. This then suggests that the Em7 results tabulated in Table 2 are reasonably accurate to conclude that the answer to the question: “Is there sufficient accuracy in current redox potential calculations to predict which amino acids will reduce a DNA base lesion?” is yes.

then, with respect to the neutral guanosine radical, disulfides (cysteinyl and its derivatives) are generally unreactive, thiols and thioesters (derivatives of cysteine and methionine) are mildly reactive, phenols (derivatives of tyrosine) are more reactive, and indoles (tryptophan compounds) are highly reactive. It is necessary to comment on the accessibility of various reducing agents. Of particular significance for DNA bonding proteins, the histone octomer contains two cysteine and no tryptophan residues, but 20 tyrosine residues.47 Actually, in general cysteine and tryptophan are the rarest two (combined abundance 2.5%) of the amino acids.47 Therefore, we should pay particular attention to the influence of tyrosinyl moiety on DNA damage. In searching references for the work on tyrosine it was noted that there are some recent studies on phenol (the side chain of tyrosine). Ghosh et al. have calculated the Eo = 1.32 V and say this is in good agreement with the experimental value of the phenol reduction potential (1.0−1.5 V).12 Their Eo = 1.32 V value is remarkably close to the experimental value determined by Surdhar et al. of 1.35 V,24 used herein. However, the estimate that Eo = 1.5 V for phenol can be seen in recent publications by Guerand et al.,48 Isegawa et al.,49 and Canonica et al.50 One can see the problem here by looking at Table 1, which has the Eo = 1.38 V for phenol compared to the Eo = 1.58 V for 9-Me-Guanine. This then is as it should be and easily oxidized amino acids like tyrosine would be able to repair guanyl radicals in DNA by electron transfer reactions. This may not be the case if the Eo for phenol is 1.5 V and conflicts with the experimental results of Milligan et al.,5 who show that the guanyl radicals are able to accept electrons from tyrosine and tryptophan. There is another important issue involving the environment influence on the intrinsic pK values of the amino acid sidechains in proteins. A mini-review by Pace et al.51 shows that the pK of tyrosine varies from 6.1 to 12.1, cysteine from 2.5 to 11.1, lysine from 5.7 to 12.1, and histidine from 2.4 to 9.2. Some of this variability comes from the change in the dielectric in a protein and with the effects various H-bonds have on the pK. For example the pK of acetic acid is increased from 4.8 in water (ε = 78) to 10.1 in ethanol (ε = 24). A quick test using the computational methods used herein show that this is indeed the case, as the computed pK of acetic acid in ethanol was 11.1. Important reducing agents in the cellular environment are the antioxidants ascorbate and glutathione. It is possible that even these small diffusible species do not have access to damaged DNA that is tightly associated with DNA binding protein. Anyway, a calculation on ascorbate performed using the three pKs in Table 2 yields an Em7 = 0.34 V, close to the experimental Em7 = 0.30 V. So then what is the response to the supposition “Is there sufficient accuracy in current redox potential calculations to predict which amino acids will reduce a DNA base lesion?” It does seem as if this is the case with the following caveat. At the level of theory used (B3LYP/Aug-cc-pVTZ)//B3LYP/631+(d,p)) the calculations underestimate the midpoint reduction potential Em7 of the common reducing agents by 0.2−0.3 V. So for comparisons of these potentials to the Em7 of the guanyl radicals it is necessary to compute their midpoint reduction potentials at the same level of theory, as shown in the last column of Table 2. The study mentioned above by Thapa and Schlegel reports DFT calculations of pK of thiols using explicit water

■

AUTHOR INFORMATION

Corresponding Author

*(D.M.C.) E-mail: [email protected]. Tel: 423-439-5646. ORCID

David M. Close: 0000-0001-6253-1841 Present Address †

(P.W.) 20 Highover Park, Amersham, Buckinghamshire HP7 0BN, U.K. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS

■

REFERENCES

The Gaussian 09 calculations reported here were supported by the Extreme Science and Engineering Discovery Environment (XSEDE), Allocation Number MCB150023. Thanks are expressed for the generous computer time allocation (to D.M.C.) to complete this project, and many thanks to Mahidhar Tatineni, San Diego Super Computer, for much help with calculations on Comet.

(1) Verdolino, V.; Cammi, R.; Munk, B. H.; Schlegel, H. B. Calculation of pK Values of Nucleobases and the Guanine Oxidation Products Guanidinohydantoin and Spirominodihydantoin using Density Functional Theory and a Polarizable Continuum Model. J. Phys. Chem. B 2008, 112, 16860−16873. (2) Psciuk, B. T.; Lord, R. L.; Munk, B. H.; Schlegel, H. B. Theoretical Determination of One-Electron Oxidation Potentials for Nucleic Acid Bases. J. Chem. Theory Comput. 2012, 8, 5107−5123. (3) Close, D. M.; Wardman, P. Calculations of the Energetics of Oxidation of Aqueous Nucleosides and Nucleotides and the Effects of Prototropic Equilibria. J. Phys. Chem. A 2016, 120, 4043−4048. (4) Milligan, J. R.; Tran, N. Q.; Ly, A.; Ward, J. F. Peptides Repair of Oxidative DNA Damage. Biochemistry 2004, 43, 5102−5108.

E


Article

The Journal of Physical Chemistry A (5) Milligan, J. R.; Aguilera, J. A.; Ly, A.; Tran, N. Q.; Hoang, O.; Ward, J. F. Repair of Oxidative DNA Damage by Amino Acids. Nucleic Acid Res. 2003, 31, 6258−6263. (6) Wardman, P. Reduction Potentials of One-Electron Couples Involving Free Radicals in Aqueous Solution. J. Phys. Chem. Ref. Data 1989, 18 (4), 1637−1755. (7) Schroeder, C. A.; Pluhařová, E.; Seidel, R.; Schroeder, W. P.; Faubel, M.; Slaviček, P.; Winter, B.; Jungwirth, P.; Bradforth, S. E. Oxidation Half-Reaction of Aqueous Nucleosides and Nucleotides via Photoelectron Spectroscopy Augmented by ab initio Calculations. J. Am. Chem. Soc. 2015, 137, 201−209. (8) Sadlej-Sosnowska, N. Calculation of Acidic Dissociation Constants in Water: Solvation Free Energy Terms. Their Accuracy and Impact. Theor. Chem. Acc. 2007, 118, 281−293. (9) SMD stands for Solvation Model “Density”, where the D in the name stands for polarized continuous quantum mechanical charge density of the solute. See: Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378−6396. (10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheesman, J. R.; Scalmani, G.; Barone, V.; Mennecci, B.; Peterson, G. A.; et al. Gaussian 09, Revision D01, Gaussian, Inc.: Wallingford, CT, 2013. (11) Mostad, A.; Nissen, H. M.; Romming, C.; et al. Crystal Structure of L-Tyrosine. Acta Chem. Scand. 1972, 26, 3819−3833. (12) Ghosh, D.; Roy, A.; Seidel, R.; Winter, B.; Bradforth, S.; Krylov, A. I. First-Principle Protocol for Calculating Ionization Energies and Redox Potentials of Solvated Molecules and Ions: Theory and Application to Aqueous Phenol and Phenolate. J. Phys. Chem. B 2012, 116, 7269−7280. (13) Dixon, W. T.; Murphy, D. Determination of the Acidity Constants of Some Phenol Radical Cations by Means of Electron Spin Resonance. J. Chem. Soc., Faraday Trans. 2 1976, 72, 1221−1229. (14) Rao, P. S.; Simic, M.; Hayon, E. Pulse Radiolysis Study of Imidazole and Histidine in Water. J. Phys. Chem. 1975, 79 (13), 1260− 1263. (15) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. Acidities of Carbon and Nitrogen Acids: The Aromaticity of the Cyclopentadieynl Anion. J. Org. Chem. 1981, 46, 632−635. (16) Shen, X.; Lind, J.; Merényi, G. One-Electron Oxidation of Indoles and Acid-Base Properties of the Indolyl Radicals. J. Phys. Chem. 1987, 91, 4403−4406. (17) Jovanovic, S. V.; Steenken, S. Substituent Effects on the Spectral, Acid-Base, and Redox Properties of Indolyl Radicals: A Pulse Radiolysis Study. J. Phys. Chem. 1992, 96, 6674−6679. (18) Gross, K. C.; Seybold, P. G.; Peralta-Inga, Z.; Murray, J. S.; Politzer, P. Comparison of Quantum Chemical Parameters and Hammett Constants in Correlating pK Values of Substituted Anilines. J. Org. Chem. 2001, 66, 6919−6925. (19) Bordwell, F. G.; Zhang, X.-M.; Cheng, J.-P. Bond Dissociation Energies of the N-H Bond in Anilines and in the Corresponding Radical Anions. Equilibrium Acidities of Aniline and Radical Cations. J. Org. Chem. 1993, 58, 6410−6416. (20) Yu, A.; Liu, Y.; Li, Z.; Cheng, J. P. Computation of pK Values of Substituted Aniline Radical Cations in Dimethylsulfoxide Solution. J. Phys. Chem. A 2007, 111, 9978−9987. (21) Thapa, B.; Schlegel, H. B. Density Functional Theory Calculation of pKa’s of Thiols in Aqueous Solution Using Explicit Water Molecules and the Polarizable Continuum Model. J. Phys. Chem. A 2016, 120, 5726−5735. (22) Kerr, K. A.; Ashmore, J. P.; Koetzle, T. F. A Neutron Diffraction Study of L-Cysteine. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1975, 31, 2022−2026. (23) Jovanovic, S. V.; Tosic, M.; Simic, M. G. Use of the Hammett Correlation and σ+ for Calculation of One-Electron Redox Portentials of Antioxidants. J. Phys. Chem. 1991, 95, 10824−10827.

(24) Surdhar, P. S.; Armstrong, D. A. Reduction Potentials and Exchange Reactions of Thiyl Radicals and Disulfide Anion Radicals. J. Phys. Chem. 1987, 91, 6532−6537. (25) Bergès, J.; de Oliveira, P.; Fourré, I.; Houée-Levin, C. The OneElectron Reduction Potential of Methionine-Containing Peptides Depends on the Sequence. J. Phys. Chem. B 2012, 116, 9352−9362. (26) Jocelyn, P. C. The Standard Redox Potential of CysteineCystine from the Thiol-Disulphide Exchange Reaction with Glutathione and Lipoic Acid. Eur. J. Biochem. 1967, 2, 327−331. (27) Merényi, G.; Lind, J.; Engman, L. The Dimethylhydroxysulfuranyl Radical. J. Phys. Chem. 1996, 100, 8875−8881. (28) Armstrong, D. A.; Huie, R. E.; Koppenol, W. H.; Lymar, S. V.; Merenyi, G.; Neta, P.; Ruscic, B.; Stanbury, D. M.; Steenken, S.; Wardman, P. Standard Electrode Potentials Involving Radicals in Aqueous Solution: Inorganic Radicals. Pure Appl. Chem. 2015, 87 (11−12), 1139−1150. (29) Merényi, G.; Lind, J.; Shen, X. Electron Transfer from Indoles, Phenol, and Sulfite (SO32‑) to Chlorine Dioxide (ClO2·). J. Phys. Chem. 1988, 92, 134−137. (30) Pekmez, N. Ö .; Can, M.; Yildiz, A. Spectroscopic and Electrochemical Observation of Hydrogen-Bonded Imidazole and 2Aminoimidazole Clusters. Acta Chim. Slov. 2007, 54, 131−139. (31) Ahmad, R.; Armstrong, D. A. The Effect of pH and Complexation on Redox Reactions Between RS• Radicals and Flavins. Can. J. Chem. 1984, 62, 171−177. (32) Steenken, S.; Neta, P. Electron Transfer Rates and Equilibria Between Substituted Phenoxides Ions and Phenoxyl Radicals. J. Phys. Chem. 1979, 83, 1134−1137. (33) Madej, E.; Wardman, P. The Oxidizing Power of the Glutathione Thiyl Radical as Measured by its Electrode Potential at Physical pH. Arch. Biochem. Biophys. 2007, 462, 94−102. (34) Steenken, S.; Jovanovic, S. V. How Easily Oxidizable Is DNA? One-Electron Reduction Potentials of Adenosine and Guanosine Radicals in Aqueous Solution. J. Am. Chem. Soc. 1997, 119, 617−618. (35) Armstrong, D. A.; Rauk, A.; Yu, D. Solution Thermochemistry of the Radicals of Glycine. J. Chem. Soc., Perkin Trans. 2 1995, 553− 560. (36) Fu, Y.; Liu, L.; Yu, H.-Z.; Wang, Y.-M.; Guo, Q.-X. QuantumChemical Predictions of Absolute Standard Redox Potentials of Diverse Organic Molecules and Free Radicals in Acetonitrile. J. Am. Chem. Soc. 2005, 127, 7227−7234. (37) Irving, R. J.; Nelander, I.; Wadsö, I.; et al. Thermodynamics of the Ionization of Some Thiols in Aqueous Solution. Acta Chem. Scand. 1964, 18, 769−787. (38) Dawson, R. M. C.; Elliott, D. C.; Elliott, W. H.; Jones, K. M. Data for Biochemical Research. 3rd ed.; Clarendon Press: Oxford, U.K., 1986. (39) Hiller, K. O.; Masloch, B.; Göbl, M.; Asmus, K. D. Mechanism of the OH• Radical Induced Oxidation of Methionine in Aqueous Solution. J. Am. Chem. Soc. 1981, 103, 2734−2743. (40) Rauk, A.; Armstrong, D. A.; Fairlie, D. P. Is Oxidative Damage by β-Amyloid and Prion Peptides Mediated by Hydrogen Atom Transfer from Glycine α-Carbon to Methionine Sulfur Within βSheets. J. Am. Chem. Soc. 2000, 122, 9761−9767. (41) Lide, D. R. CRC Handbook of Chemistry and Physics; CRC: Boca Raton, FL, 2009. (42) Solar, S.; Getoff, N.; Surdhar, P. S.; Armstrong, D. A.; Singh, A. Oxidation of Tryptophan and N-Methylindole by N, Br, and (SCN) Radicals in Light- and Heavy-Water Solutions: A Pulse Radiolysis Study. J. Phys. Chem. 1991, 95, 3639−3643. (43) Navaratnam, S.; Parsons, B. J. Reduction Potential of Histidine Free Radicals, a Pulse Radiolysis Study. J. Chem. Soc., Faraday Trans. 1998, 94, 2577−2581. (44) Rauk, A.; Yu, D.; Armstrong, D. A. Oxidative Damage to and by Cysteine in Proteins: An ab initio Study of the Radical Structures, CH, S-H, and C-C Bond Dissociation Energies, and transition Structures for H Abstraction by Thiyl Radicals. J. Am. Chem. Soc. 1998, 120, 8848−8855. F


Article

The Journal of Physical Chemistry A (45) Huang, M. L.; Rauk, A. Reactions of One-Electron-Oxidized Methionine with Oxygen: An ab Initio Study. J. Phys. Chem. A 2004, 108, 6222−6230. (46) Forsyth, W. R.; Gilson, M. K.; Antosiewicz, J.; Jaren, O. R.; Robertson, A. D. Theoretical and Experimental Analysis of Ionization Equilibria in Ovomucoid Third Domain. Biochemistry 1998, 37, 8643− 8652. (47) van Holde, K. E. Chromatin; Springer: New York, 1988. (48) Guerard, J. J.; Tentscher, P. R.; Seijo, M.; Arey, J. S. Explicit Solvent Simulations of the Aqueous Oxidation Potential and Reorganization Energy for Neutral Molecules: Gas Phase, Linear Solvent Response, and Non-Linear Response Contributions. Phys. Chem. Chem. Phys. 2015, 17, 14811−14826. (49) Isegawa, M.; Neese, F.; Pantazis, D. A. Ionization Energies and Aqueous Redox Potentials of Organic Molecules: Comparision of DFT, Correlated ab Initio Theory and Pair Natural Orbital Approaches. J. Chem. Theory Comput. 2016, 12, 2272−2284. (50) Canonica, S.; Hellrung, B.; Wirz, J. Oxidation of Phenols by Triplet Aromatic Ketones in Aqueous Solution. J. Phys. Chem. A 2000, 104, 1226−1232. (51) Pace, C. N.; Grimsley, G. R.; Scholtz, J. M. Protein Ionizable Groups: pK Values and Their Contribution to Protein Stability and Solubility. J. Biol. Chem. 2009, 284, 13285−13289. (52) Davey, C. A.; Sargent, D. F.; Luger, K.; Maeder, A. W.; Richmond, T. J. Solvent Mediated Interactions in the Structure of the Nucleosome Core Particle at 1.9 Å. J. Mol. Biol. 2002, 319, 1097− 1113.

G


Calculation of Standard Reduction Potentials of Amino Acid Radicals

Recommend Documents