Catalysis Effects of Water Molecules and of Charge on Intramolecular

Jul 31, 2009 - In this work, the three most stable uracil isomers (U1, U2, and U3) and their neutral, positive, and negative charged multihydrates are...
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J. Phys. Chem. B 2009, 113, 11732–11742

Catalysis Effects of Water Molecules and of Charge on Intramolecular Proton Transfer of Uracil Dejie Li and Hongqi Ai* School of Chemistry and Chemical Engineering, UniVersity of Jinan, 250022 P.R. China ReceiVed: April 07, 2009; ReVised Manuscript ReceiVed: June 23, 2009

In this work, the three most stable uracil isomers (U1, U2, and U3) and their neutral, positive, and negative charged multihydrates are chosen as research objects to investigate the tautomeric process between the most stable uracil, U1, and its two minor stable isomers, U2 and U3. By the study, deeper insight can be obtained regarding point mutations induced by uracil deformation. Toward the target, the activation energies of the intramolecular proton transfer (tautomeric process) as well as the catalysis effects of water molecules and of charges attached are investigated using density functional theory (DFT) calculations by means of the B3LYP exchange and correlation functions. Results reveal that water molecules hold a stronger catalysis effect on the proton transfer in these negative charged uracil hydrates than in the neutral counterparts. The optimal number of water molecules needed to catalyze the proton transfer is determined as two in the neutral hydrated systems, whereas it is three in the negative charged systems. Positive charge attachment, however, hinders the intramolecualr proton transfer of uracil, and the charge and the proton of uracil will transfer to the water clusters if water molecules are attached. Then the positive charged hydrates look more like U1a/b+[(H2O)n+H+] species in structure. Analysis reveals that it is the acceptance process of the last proton to determine the impossibility of proton transfer and result in the failure of tautomeric processes from cat-U1a-nw to cat-U2nw and from cat-U1b-nw to cat-U3-nw. Detailed structural parameters and energy changes are discussed for the above different processes. Introduction Different tautomers of nucleic acid (NA) bases can be obtained when one of its active hydrogen atoms binds different positions of the base.1 In vivo, those rare tautomers will be involved in various biochemical processes.2 Moreover, the existence of rare tautomeric forms of NA bases increases the possibility of mispairing of purines and pyrimidines that may lead to the spontaneous point mutations.3-5 Thus, a large number of theoretical and experimental studies have been devoted to the tautomerism of NA bases.6-17 Several factors, such as excitation,18 chemical modification,19 metal cation interaction,20,21 electron attachment,22 irradiation,23 etc., had been found to be responsible for the tautomeric equilibrium between the “normal” and the “rare” forms of NA bases. For example, the attachment of a low-energy electron to the NA bases or excitation of an electron from the NA bases would cause a series of property changes of these NA bases and their hydrated systems, such as the changes of relative stability of tautomers,24-26 incremental probability of proton intramolecular transfer to form new tautomers,27 the rearrangement of surrounding water molecules,28 etc. In addition, hydration also plays a significant role in the tautomeric process. Studies revealed that a water molecule might influence the stability of different tautomeric forms of NA bases through hydrogen bonding interactions.29,30 Meanwhile, water-assisted proton transfer will greatly increase the populations of the rare tautomers by lowering the activation energy barrier of the intramolecular proton transfer.29-31 As one of the important bases, uracil has also been paid much attention in recent years.12,13,32-40 Among thirteen possible * E-mail: [email protected].

Figure 1. Three most stable uracil isomers.

tautomers of uracil,13 three lowest-energy tautomers are frequently employed. One is the most stable “ketone” uracil (U1). Another two are U2 and U3, respectively, which are at least 10.8 kcal/mol higher in energy than the ketone one.13,38 Therefore, the three most stable uracil isomers are selected as research objects to investigate the hydration effect on their relative stability and the intramolecular proton transfer in the present paper. Their structures are shown in Figure 1. Obviously, if H10 of U1 transfers to its O8 site, then U1 will become U2. This indicates that intramolecular H10 transfer of U1, in fact, corresponds to the tautomeric process U1 f U2. Correspondingly, if H9 transfers to the O7 site, then the process will be U1 f U3. In the gas phase the two transfer processes are difficult due to a high activation energy barrier, while the hydration case will improve it.12,13,32,33 Despite the importance of hydration on the tautomeric process, the optimal water molecule number, which will minimize the activation energy of the intramolecular proton transfer in the tautomeric process, remains unknown. In addition, Shukla et al. reported that a charge effect greatly reduced the activation energy of proton transfer in the guanine

10.1021/jp9031833 CCC: $40.75  2009 American Chemical Society Published on Web 07/31/2009

Catalysis Effects on Proton Transfer of Uracil system or even resulted in it being barrierless.34 Li et al. showed that attachment of an electron rather than detachment of an electron from a GC pair would favor the intramolecular proton transfer.35 A photoelectron spectroscopy experiment indicated that the transformation from a dipole-bound uracil anion to a valence-bound one took place when the radical anions experienced solvation and multibody interactions in the condensed phase.36 Another experiment on the electron binding to the pyrimidine nucleobases in the presence of water clusters found that the electron affinities were almost linearly proportional to the number of solvent water molecules.37 Thus, under the condition of negative or positive charge, it would be of great interest to conduct the investigation on the optimal water molecule number required to induce the imtramolecular proton transfer of the “ketone” uracil and correspondingly to form its other two (U2 and U3) isomers. This is our other aim, in which the mechanism of the charge effect will be elucidated and the concerted effect between the charge and hydration will also be discussed. Correspondingly, in the following statement, ani-U1a or cat-U1b will be used to refer to the charged uracil isomers, where the prefixes “ani” and “cat” represent the complexes with a negative (anion) and a positive (cation) charge, respectively. The subscripts “a” and “b” represent the areas of H10 transfer to O8 (then U1 becomes U2) and of H9 transfer to O7 (then U1 becomes U3), respectively, where water molecules will be attached. Due to the importance of hydration and the charge effect on the tautomeric processes of U1 f U2/U3, in this investigation we attempt to answer the following questions: (1) How does a negative or a positive charge influence the relative stability of the uracil tautomers? (2) What is the preferred position for the proton transfer to take place in these neutral and charged uracil isomer systems with and without hydration? (3) What is the optimal number of water molecules assisting proton transfer in these neutral and charged systems? (4) How do the two different quality charges affect the intramolecular transfer proton (i.e., tautomeric processes of U1 f U2 and of U1 f U3)? etc. Computational Methods Studies had confirmed that B3LYP and MP2 could give very similar results for the geometrical and vibrational features of NA bases38 and DFT is an excellent compromise between computational cost and reasonable results. Therefore, in this article the B3LYP in combination with a considerably large basis set 6-311++G(d,p) is adopted thoroughly. The computed stationary points have been characterized as minima or transition states (TSs) by diagonalizing the Hessian matrix and analyzing the vibrational normal modes. In this way, the stationary points can be classified as minima if no imaginary frequencies are observed or as TSs if only one imaginary frequency is obtained.41,42 The particular natures of these TSs are determined by analyzing the motion described by the eigenvector associated with the imaginary frequency. After geometry optimization and frequency calculations (without scaling), zero-point energies (ZPEs) and the sum of electronic and thermal free energies (G) could be obtained. The effect of basis set superposition error was not taken into account because it had been predicted to be trivial in the uracil-water system,13,43 especially when such a considerably large basis set was used. Adiabatic potential energy surface (PES) changes along the N-H bond stretch were calculated using the optimization keyword opt)z-matrix, with the S action code in the additional input (N-H distance). Correspondingly, analysis on the charge/spin distributions and molecular orbital information

J. Phys. Chem. B, Vol. 113, No. 34, 2009 11733 TABLE 1: Optimized Bond Distances (Å) of the Three Most Stable Uracil Isomers U1

c

bond

present

N1-C2 C2-N3 N3-C4 C4-C5 C5-C6 C6-N1 N1-H9 C2-O8 N3-H10 C4-H11 C5-H12 C6-O7

1.384 1.393 1.377 1.352 1.459 1.412 1.014 1.220 1.010 1.084 1.081 1.223

theory 1.385 1.394 1.377 1.352 1.459 1.412 1.015 1.220 1.012 1.085 1.082 1.223

a

exptb

exptc

U2

U3

1.377 1.371 1.359 1.340 1.430 1.371 0.877 1.215 0.836 0.957 0.970 1.245

1.399 1.399 1.399 1.343 1.462 1.399 1.002 1.212 1.002 1.072 1.072 1.212

1.354 1.302 1.375 1.365 1.448 1.423 1.015 1.342 2.306 1.086 1.083 1.224

1.380 1.423 1.358 1.362 1.430 1.308 2.253 1.221 1.012 1.085 1.081 1.344

a Calculated at the B3LYP/6-31++G** level.13 From electron diffraction.46

b

From X-ray.38

along with the N-H changes was also made. Net atomic charges were obtained using the natural population analysis (NPA) of Weinhold et al.44 All calculations were performed with the GAUSSIAN 0345 suite of packages. Results and Discussion 1. Stability Orders of Neutral, Negative, and Positive Charged U1, U2, and U3. The geometries of the uracil and microsolvated uracil complexes were fully optimized at the B3LYP/6-311++G** level of theory. Our optimized geometrical parameters of uracil isomers listed in Table 1 are in good agreement not only with the recent theoretical results13 obtained at the B3LYP/6-31++G** level (the maximum dispersion is less than 0.002 Å) but also with those experimental ones obtained by X-ray38 and electron diffraction.46 The results of various calculations on relative free energies (∆G) and dipole moments (DMs) as well as vertical electron dissociation energies (VDEs) are compiled in Table 2. Results reveal that their stability order (in kcal/mol) is U1(0.0) > U2 (11.4) > U3(12.1), in good agreement with theoretical predictions (U1(0.0) > U2 (10.9) > U3(11.8), obtained at the B3LYP/ 6-31+G** level) by Kryachko et al.13 Moreover, the energy values of U2 and U3 tautomers are very similar to each other. With a more compact and keto structure, U1 is, thus, more stable than the two enol forms U2 and U3.47 Both U2 and U3 molecules, however, are characterized by two conjugated double bonds, CdC and CdN, in the ring and a hydroxyl linking on the ring (Figure 1). Table 2 reveals that the three tautomers have different values of dipole moment. The larger value would indicate considerable stabilization when the tautomer is attached to an electron or exposed to a polar solvent such as water.48 Comparisons reveal that U3 has the largest dipole moment (5.0) and would be most favorable to bind an excess electron in a dipole-bound or valence-bound state. Calculations reveal that the orbital of the U3 anion has a π-character and the attached electron is located on the molecular frame of the complex. Its diffuse character and orbital shape also confirm that the calculations describe a valence-bound anion (not shown). The stability order of anionic U2 (ani-U2) and U3 (ani-U3) also confirms that ani-U3 becomes the second stable tautomer and its energy is 4.9 kcal/mol less than that of ani-U2. This may be closely related to the VDE difference (4.0 kcal/mol) between ani-U2 (10.1) and ani-U3 (14.1), in which the VDE is calculated by the anionic UB3LYP

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TABLE 2: ZPVE-Corrected Relative Free Energies (∆G in kcal/mol),a Dipole Moments (DM in Debye), and VDE/AEA (in kcal/mol) neutral uracil ∆G DM VDE AEA

anionic uracil

cationic uracil

U1

U2

U3

ani-U1

ani-U2

ani-U3

cat-U1

cat-U2

cat-U3

0.0 4.6

11.4 3.3

12.1 5.0

-5.4 3.9 13.5 5.4, 5.5,b 4.2,c 1.6,d 3.2,e 3.5 ( 2.8f

10.7 3.9 10.1 0.7

5.8 3.5 14.1 6.4

213.3 6.1 217.8

215.6 3.0 209.4

219.8 5.5 210.5

a Note that the ∆G values are the differences between all these neutral/charged uracil complexes and the neutral uracil (U1). b DZP++ basis set used in ref 50. c 6-311+G(2df,p) basis set used in ref 51. d 6-311++G basis set used without ZPVE in ref 52. e TZVP basis set used in ref 53. f Extrapolated values from photoelectron spectra of nucleobase(H2O)n clusters in ref 37. All computed values in the present paper are zero-point corrected unless otherwise noted.

energies minus B3LYP energies of the corresponding neutral at the optimized anion geometries. The remaining energy (4.9-4.0 ) 0.9 kcal/mol) may be attributed to the deformation energy.49 In the meantime, we also calculate the adiabatic electron affinity (AEA) values by using the neutral species energy minus the corresponding anion one at their respective optimized geometries. Table 2 reveals that our results are in good agreement with those available theoretical ones. The slight difference may be derived from the different methods and basis sets used.37,50-53 When an electron is attached, the planar ring structures of U1 and U3 still remain, but that of U2 changes. Observation shows that N1 of U2 is exposed outside of the ring plane. So this change may consume part of the energy. In detail, the dihedral angles O7-C6-N1-H9 and O7-C6-N1-C2 are 0.0 and 180.0° in neutral U2, respectively, whereas the same dihedral angles become 22 and 163° in anionic U2, respectively. Thus, it is not surprising that the energy of anionic U2 is higher than that of anionic U1 and U3. Strong torsion of molecular framework of ani-U2 is characteristic of the covalence-bound anionic state, not of the dipole-bound one.54 The stability ordering of the three cationic (cat) tautomers is the same as the neutral one. Compared to the neutral tautomers, the energies increase in the order 213.3, 215.6, and 219.8 kcal/ mol for cat-U1, cat-U2, and cat-U3, respectively (Table 2). This indicates that ionizing an electron from these neutral molecules is very difficult. 2. Tautomeric Process. 2.1. Tautomeric Processes from Isolated U1 to Two Tautomers U2 and U3. Figure 2 shows the proton transfer processes from U1 or its hydrates to the tautomers U2 and U3 or their corresponding hydrates via TSs. The tautomeric process of U1 f U2, in fact, corresponds to the proton (H10) intermolecular transfer from the N3 site to the O8 site of U1. Optimizations show the distances of N3-H10 bonds are 1.010, 1.328, and 2.306 Å in U1, TS12, and U2, respectively, suggesting a process of intramolecular proton transfer. Meanwhile, the C2-O8 bond of U1 varies from 1.220 Å to 1.283 Å. The activation energy in the process is 41.8 kcal/ mol, indicating that the transfer is hard to achieve. The case is similar for the U1 f U3 process because of its high energy barrier of 40.8 kcal/mol. With a smaller basis set, the results obtained by Hu et al.38 and Iwona et al.55 are 42.7 (B3LYP/ 6-31G**) and 44.0 kcal/mol (B3LYP/6-31++G**), respectively, in good agreement with our conclusion. Interestingly, attachment of an electron can effectively lower the activation energy either in the tautomeric process of U1 f U2 (22.2 kcal/ mol) or of U1 f U3(6.4 kcal/mol). Ionization of an electron can also lower the energy from 42.8 (neutral) to 35.7 kcal/mol (cationic) in the U1 f U2 process; however, it can increase the energy from 41.7 to 45.5 kcal/mol in the U1fU3 process.

So attachment instead of ionization of an electron in the two processes is more effective for the proton transfer and tautomeric process. Meanwhile another interesting case is observed in the tautomeric process of ani-U1 f ani-U2. As shown for the TS geometry in the process of ani-U1 f ani-U2 in Figure 3a, the captured electron in the TS will mainly localize on H10 (∼spin: 1.01), while on other adjacent atoms the spin is small (C2 ∼spin: 0.06, O8 ∼spin: 0.00, N3 ∼spin: -0.03). This result indicates that the tautomeric process, in fact, corresponds to the cooperative transfer processes of H10 and an electron. The corresponding charge distributions in some of the atoms are as follows: H10, -0.04; C2, 0.77; O8, -0.71; and N3, -0.64. So the H10-O8 and H10-N3 bonds are elongated by 2.534 and 2.631 Å, respectively, due to the electrostatic repulsion. Along the increase of the N3-H10 distance, i.e., the transformation from ani-U1 to ani-U2, the bonding property of the N3-H10 single occupied molecular orbital (SOMO) gradually becomes a σ* bond from its initial π* bond and then a dipole-bound contribution will become dominant. The process can be visually observed from Figure 3b, in which the SOMOs of the equilibrium-state uracil anion (mostly π* state, N3-H10 ) 1.006 Å) and the TS anion (σ*-state, N3-H10 ) 1.901 Å) are displayed. Both pure π* and σ* states have a separate PES, respectively. One planar π* state corresponds to a short N1-H10 distance, whereas one planar localized σ* state corresponds to a long N1-H10 distance. They branch at a projected localized antibonding orbital, and for the σ* state (based on a symmetry conserved calculation), a dipole-bound contribution becomes dominant at the long distance (see Figure 3b and c). The energy of this state is too high to be realistic because the basis set used is not sufficient for describing a true dipole-bound state. Although the basis set limitation, the dipolebound character of the N3-H10 bond at the ani-U1 TS has noticeably emerged. Moreover, the spin distribution shown in Figure 3d also confirms that almost one atomic unit of the spin density locates over H10 when H10 is about 1.4 Å far away N3. This indicates that now anionic hydrogen H10 is dipolebound to the U1 radical.5 Of most importance is that the bonding character of N1-H10 will remind us of the real hydrated environment, i.e., if the character in a hydrated system will be further toned up and favor U1 isomerization. 2.2. Tautomeric Processes between Hydrated Systems. Figure 2 also lists the tautomeric processes of hydrated U1a-nw f U2-nw and of U1b-nw f U3-nw, where “nw” represents the number of water molecules attached and n ) 1-5, while a/b denotes two different positions of hydration in U1, as mentioned above. Obviously, if hydration is at the range between H10 and O8 of U1, then the hydration will affect the tautomeric process of U1 f U2 and we define the range as a. Similarly, if

Catalysis Effects on Proton Transfer of Uracil

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Figure 2. Tautomeric processes of U1a/b-nw f U2/U3-nw. The bond distances in angstrom, energy in kcal/mol.

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Figure 3. B3LYP/6-31+G(d)-calculated (a) TS geometry of the process from ani-U1 to ani-U2; (b) SOMOs of the ani-U1 equilibrium state (left in π*, N3-H10 ) 1.006 Å) and of TS (right in σ*, N3-H10 ) 1.901 Å) (The top two are front views and the bottom two are the corresponding top views); and (c) adiabatic PES and (d) spin distribution on the hydrogen along the N3-H10 coordinate of ani-U1 (Energies relative to that of the optimized anion in the equilibrium state). Energies are in kcal/mol, and distances are in angstrom.

hydration occurs between H9 and O7, then it is referred to as b, where H8 will transfer to the O7 site and then U1 becomes U3. In the tautomeric process of U1a-1w f U2-1w, a great change is observed relative to the one in the nonhydrated case. Results reveal that monohydration greatly decreases the activation energy of the tautomeric process (from 42.8 to 17.9 kcal/ mol). In the process, the water molecule first accepts the H10 from the N3 site of U1 and then donates its hydrogen to the O8 atom of U1. Thus, the water molecule plays the role of the “bridge” of the proton transfer, i.e., double roles of proton acceptor and donator. Once H10 attaches the O8 site, then U1a1w becomes U2-1w. Unlike the case of the tautomeric process of isolated U1 f U2, the C2-O8 and N3-H10 bonds in U1a1w are lengthened to 1.232 Å and 1.023 Å, respectively. The two hydrogen bond distances between U1 and the water are 1.928 Å and 1.942 Å, respectively, only 0.001 Å longer than that of the corresponding bond in Chandra’s work39 (B3LYP/ 6-31+G**). Moreover, the attachment of a water molecule significantly increases the partial electron density of O8 and makes the O8 susceptible to accept a proton. Hence, compared with the isolated U1 f U2 tautomeric process, it is not surprising that attachment of a water molecule can decrease the activation energy of the tautomeric process by 24.9 kcal/mol. That is to say, a water molecule can greatly favor the tautomeric process of U1 f U2.13,38

When the second water attaches the U1a-1w, then U1a-1w becomes U1a-2w. A comparison reveals that the bond lengths of O8-H (attached) and N3-H10 in the TS12a-1w of the U1a-2w f U2-2w process are further lengthened by 0.05 and 0.039 Å, respectively. The C2-O8 bond is also elongated somewhat. The activation energy of proton transfer from the N3 to the O8 site is further decreased by 1.2 kcal/mol relative to the monohydrated tautomeric process; that is, dihydration further reinforces the assisting effect on the tautomeric process of U1 f U2. If trihydration occurs in the same region, only fewer changes of the C2-O8 and N3-H10 bonds in U1a-3w are observed (see U1a-3w f U2-3w in Figure 2). Compared with those in U1a-2w, the C2-O8 and N3-H10 bonds almost change little. Therefore, the assistance effect of water molecules on the tautomeric process should be similar to that in the dihydated complexes. In fact, comparisons to the activation energy in the U1a-2w f U2-2w process show the activation energy in the trihydrated tautomeric process increases by 3.4 kcal/mol. This may be due to the higher energy cost of H10 transfer in a long trihydrated chain. Does the trend continue? Tetrahydrated and pentahydrated cases are also taken into account to investigate the multihydated effect. According to the initial scheme, attachment of water molecules around H10 would be maximum to reflect the proton

Catalysis Effects on Proton Transfer of Uracil transfer. Therefore, further optimization for the tetrahydrated U1 shows that two different structures can be obtained. One is that U1 interacts directly with only two water molecules and the other two water molecules interact with the former two through intermolecular H-bonds, resulting in two eightmembered ring structures. Moreover, the two rings are almost perpendicular to each other (∼) (see U1a-4w in U1a-4w1 f U2-4w1 of Figure 2). Thus intramolecular proton (H10) transfer should be mainly assisted by two inside water molecules and like the dihydrated case discussed above. The structure shows the outside two water molecules are H-bonding with the inside ones. The calculated activation energy of the proton transfer in this process is 16.3 kcal/mol, which is further less by 0.4 kcal/ mol than that of the dihydrated process. This indicates that the effect of second-shell water molecules on the intramolecular proton transfer is still favorable, although it is subordinate. Another tetrahydrated structure covers the intramolecular proton transfer via all four water molecules (see U1a-4w f U2-4w2 in Figure 2). The activation energy of this process is 22.9 kcal/ mol, more than that of the trihydrated case. The result illuminates again that the activation energy is not always decreasing with the number increase of water molecules. According to the first tetrahydrated case, the fifth water is attached at another side of the inside two water molecules to probe if the third second-shell water molecule can further decrease the activation energy of proton (H10) transfer. Results reveal that the activation energy increases a lot. These results indicate that the long-range proton transfer assisted directly by four or even more water molecules is not optimal; that is, all the water molecules do not directly participate in and favor the proton transfer process56 due to the limited space and increased activation energy. Of course, more sophisticated investigations are required to further verify this point soon. With the increase in the number of water molecules from 1 to 5, the activation energies of proton transfer in these uracil hydrates are not always reduced. The dihydrated complex is a milestone; that is, dihydration minimizes the activation energy in the tautomeric processes of U1a-nw f U2-nw. In summary, the order of the activation energies (kcal/mol) in these different hydrated systems can be listed as follows: U1a-4w1 f U2-4w1(16.3) ≈ U1a-2w f U2-2w (16.7) < U1a-1w f U2-1w (17.9) < U1a-3w f U2-3w (20.1) < U1a-4w f U2-4w(22.9) ≈ U1a-5w f U2-5w(23.2) < U1 f U2(42.8). Like the discussion on the tautomeric processes of U1a-nw f U2-nw, we also probe the tautomeric process of U1 f U3 with and without hydration (Figure 2). Results reveal that the activation energy in the tautomeric process of U1b-1w f U3-1w is 18.9 kcal/mol, much less than that of the nonhydrated U1 f U3 process (41.7 kcal/mol) and a little larger (1.0 kcal/ mol) than that of the U1a-1w f U2-1w process. The C6-O7 bond in U1b-1w is lengthened to 1.234 Å, and the N1-H9 bond in U1b-1w is 0.014 Å also longer than that of U1. The bond distance between the oxygen atom of water and H9 is 1.968 Å.39,40 Thus, the monohydrated effect in the tautomeric process of U1b-1w f U3-1w is also remarkable. Further hydration leads to the longer C6-O7 and N1-H9 distances in U1b-2w. In the transition state (TS13b-2w) of the U1b-2w f U3-2w process, the N1-H9 bond is lengthened by about 0.085 Å. Accordingly, dihydration further reinforces the catalysis effect on the tautomeric process of U1 f U3, which is confirmed by the lower activation energy of 16.3 kcal/mol. The calculated results for the trihydrated tautomeric process reveal that the catalysis effect of hydration on the tautomeric process also decreases. In comparison with the activation energy of the U1b-2w f U3-

J. Phys. Chem. B, Vol. 113, No. 34, 2009 11737 2w process, the energy of the trihydrated process increases by 1.3 kcal/mol, which is less than the energy difference (3.4 kcal/ mol) between U1a-3w f U2-3w and corresponding U1a-2w f U2-2w. To verify the further increasing trend of the activation energy in the multihydated circumstance, tetrahydrated complexes are also considered. Optimization shows that the interaction of the uracil with four water molecules forms a twelvemembered-ring structure due to the coexistence of two neighboring electronegative groups (N1 and O8). A hydrogen atom of a water molecule neighboring to H9 (see U1b-4w f U3-4w in Figure 2) forms a hydrogen bond with O8. The activation energy of the tautomeric process is 21.9 kcal/mol, higher by 3.1 kcal/mol than that of the trihydrated process. The results further confirm that the catalysis of water molecules also exists in the tautomeric process of U1 f U3 and the optimal number of water molecules needed for the assisting proton transfer is two. Correspondingly, the minimum activation energy is 16.3 kcal/mol, less by 0.4 kcal/mol than that of U1a-2w f U2-2w. The value is equal to that (16.3 kcal/mol) of the U1a4w1 f U2-4w1 process. This implies that in aqueous solution the tautomeric processes of U1 f U2 and U1 f U3 are competitive, and the transfer rates in the two processes would be equivalent. Different from the case of U1a-nw f U2-nw, the activation energy of U1b-3w f U3-3w is less than that of U1b-1w f U3-1w but more than that of U1b-2w f U3-2w. An analysis reveals the bond length of N1-H9 in U1-3W is greatly elongated, which is propitious to proton transfer. With the increase in the number of water molecules from 1 to 3, the assisting ability should be reinforced. Possibly due to the larger energy cost for proton transfer in a longer chain, the activation energy of the U1b-3w f U3-3w process also begins to increase. The proton-transfer case in more than pentahydrated systems is not taken into account because there is an increased trend for the activation energy after attaching more than two water molecules. The order of the activation energy (kcal/mol) for these different hydrated U1 f U3 tautomeric processes can be summarized as follows: U1b-2w f U3-2w (16.3) < U1b-3w f U3-3w (17.6) < U1b-1w f U3-1w (18.9) < U1b-4w f U34w (22.0). From the ordering, we can also observe that the activation energy of U1b-3w f U3-3w is less than that of U1b-1w f U3-1w, which is different from the corresponding hydrated U1 f U2 processes. 3. Hydrated Uracil Anions. 3.1. Geometries and Energies. Figure 4 shows the selected geometry parameters of these aniU1a/b-nw complexes. Their activation energies, TSs, and product in the tautomeric processes are listed in Figure S1 of the Supporting Information (SI). The most significant changes in the geometry of the anionic U1a-1w complex are the dramatic elongation of the H10 · · · O13 distance. The H10 · · · O13 distance varies from 1.937 Å in the neutral U1a-1w to 2.508 Å in aniU1a-1w. As expected, the proton donor N3 of uracil is closer to the proton (the N3-H10 bond distance decreases by 0.014 Å compared to the neutral species); the O8 · · · H15 bond length in ani-U1a-1w is also shorter by 0.235 Å than that in the corresponding neutral species U1a-1w. Since the attachment of an extra electron on the monohydrated uracil, the activation energy of the tautomeric process, ani-U1a-1w f ani-U2-1w, increases by 0.2 kcal/mol instead of decreases. By comparison, when an extra electron attaches to U1b-1w, the activation energy of its tautomeric process, ani-U1b-1w f ani-U3-1w, reduces to 13.9 kcal/mol. The the H9 · · · O13 distance of ani-U1b-1w elongates by 0.645 Å, while its O7 · · · H14 distance is shortened by 0.258 Å relative to that in the neutral U1b-1w.

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Figure 4. Optimized geometries of anionic and cationic U1 hydrates. Distances in angstrom.

According to the geometric features of the neutral species, the dihydrated anionic uracil complexes can be classified into two types, ani-U1a-2w and ani-U1b-2w (Figure 4). The aniU1a-2w structure looks like its neutral counterpart U1a-2w. Notice that the H10 · · · O16 bond (2.137 Å) and the H-bond between the two water molecules (1.771 Å) in ani-U1a-2w are greatly elongated compared to those in the corresponding neutral species (1.789 and 1.738 Å). The H15 · · · O8 (1.613 Å) distance is, however, far shorter than that (1.790 Å) in the neutral species. The structural feature implies that anionic U1a-2w should be more prone to transfer H10 to produce the ani-U2-2w. The activation energy result, which is about 1.7 kcal/mol lower than the neutral tautomeric process, confirms the prediction. Different from neutral U1b-2w, the ani-U1b-2w structure changes greatly. That is, two water molecules are respectively attached at the O7 and O8 sites of the uracil with 1.659 and 2.044 Å H-bond distances. Meanwhile they also H-bond to each other with a 2.177 Å distance. The bifurcated weak H-bond O13 · · · H9 · · · O15 is significantly longer than that of the normal H-bond. In other

words, only a water molecule acts as donor and acceptor of the proton (H9) transfer in the dihydrated ani-U1b-2w complex, which is just like the case in the monohydrated ani-U1b-1w complex. The optimized TS listed in Figure S1 confirms the prediction. Moreover, the activation energy of the process aniU1b-2w f ani-U3-2w is 10.4 kcal/mol, lower than those in the neutral (17.6 kcal/mol) and anionic (13.9 kcal/mol) monohydrate tautomeric processes, indicating that the second attached water also actually assists the proton transfer although it does not act as a bridge of proton transfer. Thus, dihydrate is more favorable to the transfer of a proton as compared to a monohydrate. Relative to the neutral dihydrate process, the tautomeric process is also advantageous due to less activation energy (lower by 6.3 kcal/mol), further implying the importance of an extra electron for the proton transfer or tautomeric process. The trihydrated anion structure of ani-U1a-3w shows that there are only two water molecules directly H-bonding to the O8 atom of the uracil. The third water molecule locates at the second shell, H-bonding to the two internal water molecules.

Catalysis Effects on Proton Transfer of Uracil The bond distances of O16-H10, O13-H17, and O8-H15 are 2.150, 1.727, and 1.618 Å, respectively. The dihedral angle C4-N3-O16-O18 is -29.8°. The whole molecule forms a three-water cluster. The activation energy of proton transfer of ani-U1a-3w assisted by two internal water molecules is 12.3 kcal/mol, much lower than those of ani-U1a-2w (14.9 kcal/mol) and the neutral counterpart (20.1 kcal/mol). The results suggest that the formation of the water cluster with the third water molecule in the second shell weakens the H-bonding between U1 and the first-shell water but still favors proton transfer although the third water does not take on a proton transmitter. On the other hand, the result also reveals that the electron assistance effect is further enhanced in the trihydrated complex relative to that in the dihydrtated case. Similar trends can also be observed from the ani-U1b-3w tautomeric process. Differently, the structure of ani-U1b-3w is obtained by inserting the third water molecules between the two H-bonded water molecules of ani-U1b-2w. The values of the O7-H14, O13-H16, and O15-H9 bond lengths are 1.557, 1.721, and 2.278 Å, respectively. The bond distances of O15-H19 and O8-H18 are 2.003 Å and 1.940 Å, respectively. The structure shows that the bridge of proton transfer is just the two top water molecules. The bottom water molecule and uracil produce a H-bond (O8-H18), and the bond is almost in parallel to another two H-bonds formed by the uracil and the two top water molecules. Interestingly, the activation energy is 9.0 kcal/mol, far lower than that of the ani-U1a-3w tautomeric process, indicating the ani-U1-3w prefers isomerizing into ani-U3-3w to ani-U2-3w. Both ani-U1a-4w and ani-U1b-4w structures have two H-bonding water molecules in the internal shell, and another two in the second shell H-bonding with the two internal water molecules. The angles O8-O13-O22 and N3-O16-O19 in ani-U1a-4w amount to 103.9° and 68.4°, respectively, whereas angles O7-O19-O22 and N1-O13-O16 in ani-U1b-4w are 101.6° and 109.2°, respectively. Of most importance, one of the two hydrogens in the first water, which is acting as a bridge of H9(-N1) transfer in ani-U1a-4w, is pointing to O20 and another one to the outside of the tetrahydrate. Correspondingly, one of that in ani-U1b-4w points to O16 and another to O8. Thus, proton transfers in the two tetrahydates (i.e., H10 of aniU1a-4w and H9 of ani-U1b-4w) have to depend on the fourwater-ring or on two internal water molecules. Optimized TSs reveal that the tautomeric process is achieved by transferring a proton through the whole four-water cluster; that is, four H-bonding water molecules together assist the proton transfer by displacing their hydrogen with the former one by one. The calculated activation energies of the tautomeric process in the tetrahydrated ani-U1a-4w and ani-U1b-4w are 13.2 and 9.2 kcal/ mol, respectively, somewhat higher than those of the trihydrated counterparts, suggesting that a longer water chain would increase the difficulty of proton transfer. In contrast to those of dihydrated counterparts, the energy results indicate that two outer-shell water molecules greatly favor the proton transfer. Compared to the corresponding neutral processes, the activation energies decrease by 9.7 and 12.7 kcal/mol, respectively, further confirming the advantage of electron attachment for the tautomeric process. Here we summarize the order of activation energies (kcal/mol) in these different anionic hydrated systems as follows: ani-U1b-3w (9.0) ≈ ani-U1b-4w (9.2) < ani-U1b-2w (10.4) < ani-U1a-3w (12.3) < ani-U1a-4w (13.2) ≈ ani-U1b-1w (13.9) < ani-U1a-2w (14.9) < ani-U1a-1w (18.1). As Figure 5 has exhibited, the optimal number of water molecules required to assist proton transfer in these neutral systems is two, but in anionic species it becomes three. In general, the U1 f U3

J. Phys. Chem. B, Vol. 113, No. 34, 2009 11739

Figure 5. Activation energy changes along with the increase of attached water number (n) for these neutral and charged uracil hydrates in each corresponding tautomeric processes.

process is more favorable than the U1 f U2 one from the viewpoint of activation energy and the trend would be greatly enhanced under the condition of an electron attachment. It is believed that the result is related closely to the largest dipole moment of U3. Generally speaking, the negative charge is very efficient in inducing the tautomeric processes of U1-nw f U2-nw/U3-nw. 3.2. Charge Distribution and Electron Vertical Detachment Energy. The analysis of the NPA charge distribution provides insights into the overall charge effect. Table 3 summarizes the VDE and negative charge distribution over the water molecules and the uracil base of these anionic hydrates. A comparison shows that the present VDE results are in good consistency with those available theoretical data.48 The charge distribution shows that hydration results in electron transfer from the base to attached water molecules by about 0.05-0.1 au. The largest charge transfer is found in the trihydrated ani-U1b-3w (0.09 au). In general, the more the attached number of water molecules, the more the negative charge distribution on the water. In most cases negative charge transfer in the b-position hydrated complexes (ani-U1b-nw, n ) 1-4) is more than that in the a-position hydrated ones (ani-U1a-nw). Correspondingly, the VDE increase is more notable along the number of attached water molecules in these ani-U1b-nw complexes than that in the ani-U1a-nw counterparts, indicating a stronger binding strength for the extra electron in these ani-U1b-nw complexes. For example, the VDE of ani-U1b-3w amounts to 14.4 kcal/ mol, which is about 3.2 and 3.9 kcal/mol higher than those of ani-U1b-2w and ani-U1b-1w, respectively. Experimental results37 also confirmed that the VDE increased along with the attached number of water molecules. The VDE differences between ani-U1a-3w and ani-U1a-2w, and between ani-U1a3w and ani-U1a-1w are far less than the ones between the corresponding ani-U1a-nw series. This would be why the former requires less activation energy to perform proton transfer than the latter. In addition, the larger VDE and dominant charge distribution are always over the uracil species in these diverse hydrates, suggesting that the extra electron should mainly locate at uracil and has a stronger affinity to the uracil species. The SOMOs of ani-U1a/b-nw tautomeric processes in Figure S2 of the Supporting Information also show this point. The VDE changes along with the attached water molecules are closely related to the proton transfer, i.e, the tautomeric process. Generally speaking, the VDE increases along with the increased number (0-3) of attached water molecules and is almost linearly proportional to the number of water molecules.37

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TABLE 3: NPA Charge Distribution (au), VDE, and AEA (kcal/mol) of Charged Hydrates (n ) 1-4) charge

a

charge

hydrate

U

nH2O

ani-U1a-1w ani-U1a-2w ani-U1a-3w ani-U1a-4w ani-U1b-1w ani-U1b-2w ani-U1b-3w ani-U1b-4w

-0.95 -0.94 -0.92 -0.91 -0.94 -0.92 -0.91 -0.92

-0.05 -0.06 -0.08 -0.09 -0.06 -0.08 -0.09 -0.08

VDE

AEA a

25.7, 22.6 24.1, 20.5a 34.2 36.1 28.3, 25.8a 33.6, 29.1a 38.7 37.8

a

8.6, 8.1 7.4, 6.9a 7.7 8.4 12.2, 11.5a 12.0, 11.3a 15.2 13.6

hydrate

U

nH2O

cat-U1a-1w cat-U1a-2w cat-U1a-3w cat-U1a-4w cat-U1b-1w cat-U1b-2w cat-U1b-3w cat-U1b-4w

0.93 0.89 0.07 0.06 0.95 0.90 0.89 0.88

0.07 0.11 0.93 0.94 0.05 0.10 0.12 0.12

DZP++ basis set used in ref 48. All computed values are zero-point corrected unless otherwise noted.

The VDE values, however, keep fewer changes between the anionic trihydrates and tetrahydrates. Correspondingly, the activation energy of proton transfer of trihydrates is the minimum. An exception is ani-U1a-2w, which has a lower VDE and activation energy than those of ani-U1a-1w. Why? It should derive from the fact that the dihydrate has a more advantageous spatial configuration than the monohydrate for proton transfer. That is, two water molecules in the dihydrate reduce the distance between the proton and water molecule and favor the transfer. In addition, the activation energies of neutral U1a-3w and U1b3w are somewhat larger than those of their corresponding dihydrated counterparts. However, there is a zooming VDE for the anionic trihydrates; that is, there is a larger difference between ani-U1a/b-3w and each corresponding anionic dihydrate, which results in the lower activation energy of proton transfer in the anionic trihydrate. 4. Cationic Uracil Hydrates. 4.1. Geometries and Proton Transfer. To further investigate the positive charge effect on the tautomeric process, we also calculate positively charged U1, U2, and U3 without and with hydration. Unexpectedly, the optimized geometries in Figure 4 show that a single water molecule only attaches to the adjacent hydrogen of U1 rather than H-bonds to the adjacent oxygen (see cat-U1a-1w and catU1b-1w). Thus, monohydration does not favor the intramolecular proton transfer, i.e. tautomeric process. Since there is a hydrogen atom of water pointing to the adjacent carboxyl oxygen of cat-U1a-1w, we hope that the second attached water can link the first water and the carboxyl oxygen and even offer a bridge of proton (H10) transfer. Optimization shows that the hydrogen of the second water is further far from the carboxyl oxygen (O8) of the uracil relative to that of the first water in cat-U1a-1w. This is, dihydration at the (N3)-H10 site cannot assist the proton transfer to isomerize into cat-U3a-2w. The structure of cat-U1b-2w shows a potential for the proton transfer because O7-O15-O13-N1 forms an eight-membered ring, in which three hydrogen atoms link them. However, the distance between H15 and O7 is 2.528 Å, far longer than a regular H-bond distance. In addition, NPA analysis reveals that the whole electron spin is mainly located on the uracil species and the net charge on the base is equal to 1 au. Thus, cat-U1b2w is better described as cat-U1b++2w. Alpha molecular orbital coefficients indicate that there are two strong antibonding interactions between O7 and H14, and between O13 and H9, respectively. Therefore, in such a way, proton transfer assisted by dihydration also seems hard to achieve. How about the trihydrated case? Maybe the third water can link the second water and O8 of cat-U1a-2w or O7 of cat-U1b2w to form a ring structure and, thus, improve the potential of proton transfer. According to the idea, we do get two ringstructure trihydrates, cat-U1a-3w and cat-U1b-3w. However, our several attempts to optimize the TS of proton transfer fail,

i.e., the cat-U2-3w and cat-U3-3w cannot be formed. So do, for the two tetrahydrated complexes, cat-U1a-4w and cat-U1b4w. To investigate the positive charge effect, we calculate the NPA of these hydrates and list the charge in Table 3. Note that the charge of the nH2O species in the cat-U1a-3/4w includes that of H10 because H10 has almost transferred to the water clusters (see the N3-H distances in Figure 4), whereas that of H9 in the cat-U1b-3/4w does not due to shorter N1-H distances. However, there is a fast growth tendency for the N1-H distance along with the number increase of attached water molecules. So these cationic multihydrates can be regarded as cat-U1a/ b+[(H2O)n+H+], especially for the cat-U1a-nw series. Meanwhile we also optimize the change relationships of PESs along the N3-H10 and O8-H (the hydrogen of the last water, which is pointing to the O8) for cat-U1a-3/4w, as well as along the N1-H9 and O7-H (the hydrogen of the last water, which is pointing to the O7)) for cat-U1b-3/4w, respectively. The results are depicted in Figure 6. It is surprising that the activation energies of H9 atom dissociation (from the N1 site to the linked water) in both catU1b-3w (1.5 kcal/mol) and cat-U1b-4w (3.6 kcal/mol) are quite low, whereas that of H10 dissociation (from the N3 site to linked water) in both cat-U1a-3w and cat-U1a-4w become barrierless (see Figure 6I). This indicates that the two hydrogen atoms are very readily dissociated by the oxygen of adjacent water. Figure 4 confirms that the hydrogen in the reactants (from cat-U1b1w to cat-U1b-4w) runs to the adjacent water and the trend becomes more and more obvious along with the number increase of water molecules attached. The conclusion can also be drawn from the gradually shortened H9-O13 distance along with the increase of water molecule number. That is, the H9-O13 distances are 1.667, 1.540, 1.481, and 1.465 Å in cat-U1b-1w, cat-U1b-2w, cat-U1b-3w, and cat-U1b-4w, respectively. Similar phenomenon can also be observed from these different cat-U1anw complexes. Differently, H10 in these hydrates, especially in the triand tetrahydrates, has completely separated from the uracil and transferred to the adjacent water molecule. This indicates that it is the proton acceptance processes (O7-H or O8-H) instead of the proton donation process (N1-H or N3-H) that is crucial for the tautomeric process. Z-matrix optimized O7-H/O8-H distance-PES results in Figure 6-II reveal that the determining step of proton transfer indeed locates at the proton acceptance process. That is, all these PESs of catU1a-3w, cat-U1a-4w, cat-U1b-3w, and cat-U1b-4w increase gradually as the proton of water transfers to the O8/O7 of the uracil, which results in the proton transfer being unavailable. In the proton transfer process (from the nearest water molecule to the O8 site of cat-U1a-3/4w or to the O7 site of cat-U1b-3/ 4w), there is no local energy minimum found and the energies in these PESs almost keep increasing as the proton transfers (see Figure 6-II), which further confirms the impossibility of

Catalysis Effects on Proton Transfer of Uracil

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Figure 6. PES changes along with (I) N3-H10 (cat-U1a-3/4w)/N1-H9 (cat-U1b-3/4w) and (II) H-O8 (cat-U1a-3/4w)/H-O7 (cat-U1b-3/4w), calculated at the B3LYP/ 6-31+G(d) level.

the transfer of a proton. This further confirms that the products cat-U2-3/4w and cat-U3-3/4w are hard to produce due to their high activation energies. Conclusions To investigate the catalysis effects of water molecules, charge, or their union on the intramolecular proton transfer of uracil, 24 uracil hydrates have been discussed. Series of significant TSs in the related proton-transfer processes have also been studied. On the basis of the results obtained from our calculations, the following conclusions can be drawn. The optimal water molecule number needed for favoring the proton transfer is determined. Initially, intramolecular proton transfer of the most stable uracil (U1) has a high energy barrier. That is, it would need much more activation energy to complete the tautomeric processes of U1 f U2 and U1 f U3. But the energies will decrease considerably when water molecules are bound to the U1. Comparisons can get the following order of activation energy (kcal/mol) of proton transfer in different tautomeric processes: U1b-2w f U3-2w (16.3) < U1a-2w f U2-2w (16.7) < U1b-3w f U3-3w (17.6) < U1a-1w f U2-1w (17.9) < U1b-1wfU3-1w (18.9) < U1a-3wfU2-3w (20.1) < U1b-4w f U3-4w (22.0) < U1a-4wfU2-4w (22.9) < U1a-5w f U2-5w (23.2). The result indicates that two water molecules are optimal for catalyzing the intramolecular proton transfer of the neutral U1. Moreover, the U1b-nw f U3-nw process seems more readily available than the U1a-nw f U2nw one due to the larger dipole moment of U3. Proton transfer occurred at two different sites, N1 and N3, of U1, in fact, corresponding to the tautomeric processes of U1a-nw f U2nw and U1b-nw f U3-nw, respectively. For example, if H9 transfers from N1 to the O7 site, then U1 becomes U3. An extra electron attachment to the uracil would dramatically decrease the activation energy of the above tautomeric processes. The order of activation energies (kcal/mol) in these different anionic hydrated systems is as follows: ani-U1b-3w (9.0) ≈ aniU1b-4w (9.2) < ani-U1b-2w (10.4) < ani-U1a-3w (12.3) < aniU1a-4w (13.2) ≈ ani-U1b-1w (13.9) < ani-U1a-2w (14.9) < ani-U1a-1w (18.1). This indicates that the concerted effect of electron and hydration is pivotal to the proton transfer. In contrast with the case of the neutral hydrates, the optimal number of water molecules to assist proton transfer in these anionic complexes has become three and the activation energies of proton transfer in these ani-U1b-nw complexes seem lower than those in the corresponding ani-U1a-nw counterparts. Moreover, the electron attachment also influences greatly the structures of

the hydrates. For example, attachment of an extra electron to the uracil-water complex results in a significant decrease in the O · · · H · · · O · · · H bond lengths (typical bond length amounts to 1.540-1.680 Å, about 0.200 Å shorter than those in the neutral counterpart) and a great increase in the NH · · · OH atomic distances. Comparisons reveal that hydration is more efficacious to reduce the activation energy of proton transfer than the electron attachment does, whereas electron attachment can further decrease the activation energy somewhat on the basis of hydration. The concerted effect is more obvious for those systems with larger dipole moments, such as U3 in the present study. Due to the electron mainly locating at the uracil species, the number increase of hydrated water molecules can strengthen the effect, which is confirmed by the increased VDE. Correspondingly, the VDE is also closely related to the activation energy of proton transfer. That is, both hydration and electron attachment favor the tautomeric processes from the normal U1 to the rare U2 or U3, i.e., increase the rate of mutations.2 Addition of a positive charge will hinder the proton transfer. NPA and the PES changes along with the H-bond distance reveal that in these cationic hydrates spin is mainly located on uracil species, whereas the positive charge as well as the proton will transfer to the water cluster. Moreover, the trend becomes more obvious along with the increasing number of water molecules. Total cationic hydrates can approximately be regarded as catU1+ [(H2O)n+H+] structures. Calculations reveal that proton transfer from the nitrogen site of the uracil hydrates to its water cluster is effortless. The key question, which will determine the tautomeric process, is the last step. That is, it is difficult and almost impossible for the proton transfer of a water cluster to the uracil. As a result, we cannot observe the proton transfer in these cationic U1 hydrates. In a word, hydration, electron attachment, or their concerted effect, but the electron ionization, would induce the mutation of the most stable U1 to its two rare U2 and U3 isomers. Acknowledgment. This work is supported by NSFC(20573047) and NSF(Y2008B56) of Shandong Province and Foundations for doctoral start-up by Jinan University (B0418). Supporting Information Available: Ani-U1a/b-nw tautomeric processes and relative energies (Figure S1) and SOMOs of ani-U1a/b-nw tautomeric processes (Figure S2). This information is available free of charge via the Internet at http:// pubs.acs.org.

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