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Ab Initio Study of Microsolvated Al3+-Aromatic Amino Acid Complexes J. Larrucea,† E. Rezabal,*,‡ T. Marino,§ N. Russo,§ and J. M. Ugalde† Kimika Fakultatea, Euskal Herriko Unibertsitatea and Donostia International Physics Center (DIPC), P. K. 1072, 20080 Donostia, Euskadi, Spain, Institut fu¨r Anorganische und Analytische Chemie, Johann Wolfgang Goethe-UniVersita¨t Frankfurt Max-Von-Laue-Str. 7, D-60438 Frankfurt am Main, Germany, and Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni Parallele e Distribuite-Centro d’Eccellenza MIUR, UniVersita` della Calabria, I-87030 ArcaVacata di Rende (CS), Italy ReceiVed: March 2, 2010; ReVised Manuscript ReceiVed: May 17, 2010
The systematic microhydration of Al3+-aromatic amino acid complexes is studied by both B3LYP/G03 and PBE/CPMD methods, considering the different binding sites available. The binding affinity of water molecules together with the structural and thermochemical changes triggered by the solvation of the metal are discussed, which are found to be dominated by the charge and size of the metal cation, yielding a very subtle equilibrium between the steric hindrance and the charge transfer to the metal. Some structures previously seen to be unfavored in the gas phase are stabilized upon microhydration, without the need of including bulk solvent effects. Introduction Most biological processes take place in aqueous environments, where biological reactions are triggered by specific interactions which take place within the first solvation shells around the solvated biological species. Full solution studies can hardly provide much detailed insight into these features, while microhydration studies do yield sensible information on thermochemical and structural changes arising upon the sequential increment of water molecules in the nearest shell of the biological solute species.1 Within this context, metalloproteins represent an example where microhydration studies are crucial, due to the subtle balance between metal-hydration by the solvent molecules and metal-ligation by the amino acid side chain ligands. Thus, the careful study of the effects of microhydration becomes mandatory for unveiling the role of the solvent molecules in the final structure and, therefore, the reactivity of the metalloprotein in the solvent. Our particular interest toward the Al3+ arises from its capacity of altering and blocking the activity of many enzymes, crucial for many chemical reactions in living systems.2 Due to the highly sophisticated structure and big size of the proteins, small biological models are normally used for understanding the basic features governing their structure and chemical activity. In particular, gas phase studies of metal-amino acid complexes as a model for bigger systems have provided a new theoretical and experimental insight on the contributions of the different interactions within a metalloprotein, including the role of different degrees of hydration of the metal binding site. Many experimental and theoretical studies on the hydration of metalated amino acids are available in the literature, most of them related to alkali metals and aliphatic and acidic amino acids.1,3–9 Few of them considered aromatic amino acids (AAAs)1,9,10 or dicationic metals.11–13 Nevertheless, to the best of our knowledge, the study of triply charged metals has not * To whom correspondence should be addressed. E-mail: rezabal@ chemie.uni-frankfurt.de. † Euskal Herriko Unibertsitatea and Donostia International Physics Center. ‡ Johann Wolfgang Goethe-Universita¨t Frankfurt Max-von-Laue-Str. 7. § Universita della Calabria.
been addressed yet. Instead, several studies regarding complex formation between Al3+ and various bidentate and potentially tridentate amino acids (Gly, Ser, Thr, Gln, Asn, Glu, and Asp) and some model compounds have been carried out in aqueous solution by means of pH-potentiometric and multinuclear (1H, 13 C, and 27Al) NMR techniques. The present manuscript reports on the microhydration of the complexes formed by the triply charged aluminum cation Al3+ and AAAs, in particular, phenylalanine (Phe), tyrosine (Tyr), and tryptophane (Trp). The aromatic ring in the side chains of these amino acids provides the possibility of exploring also the cation-π interaction,14 which is now recognized as one of the strongest noncovalent binding forces in the gas phase and claimed to occur also on protein surfaces, exposed to aqueous solvation.15–17 Due to the abundance of AAAs in proteins, the cation-π interactions should play a crucial role in the structure and activity of the proteins and must therefore be included together with the different interactions likely to take place between a metal and the protein. Earlier investigations on nonhydrated Al3+-AAA systems in the gas phase provided valuable information on their intrinsic chemical and physical properties.18 As a continuation of the bare system gas-phase study, the present research consists of the study of a set of sequential hydrations of the various bare Al3+-AAA complexes characterized earlier. The stepwise addition of water molecules to the aluminum cation was carried out, until an octahedral environment around the metal was achieved, to learn more on the role the increment of the number of water molecules plays on the coordination and stability of the metal center. Computational Details Geometry optimization for each structure was performed at two theory levels, which will be named B3LYP/G03 and PBE/ CPMD throughout the text. The former were performed with Gaussian03;19 the B3LYP hybrid functional coupled with the standard all-electron 6-31+G(d,p) basis for the aluminum ion and the compact effective core potentials and shared-exponent basis set of Stevens, Basch, Krauss, and Jasien (SBKJ/*+) for
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C, N, O, and H was chosen for geometry optimizations and frequency calculations, which confirmed the stationary point nature of the structures studied. Single point calculations with the 6-311++G(2df,2p) larger basis set were done to improve the accuracy of the binding energies. This level of theory was previously seen to represent a good compromise between the accuracy and computational effort required for this kind of system.20,21 The Car-Parrinello molecular dynamics simulations were performed22 by means of the CPMD package;23 the temperature of the system was set to 300 K by using a Nose24-Hoover25 thermostat,26 and atoms were described by using the approximate PBE density functional27 and Vanderbilt ultrasoft pseudopotentials28 implemented29 for CPMD,30 with a 30 Ry plane wave cutoff. Electronic fictitious mass (µ) was set at 900 amu with a time step of 0.17 fs (7 au). Hydrogens (protiums) were substituted by deuteriums to increase the usable time step length since the experimental properties of heavy water are well-known and the chemistry will not be altered, as was already seen in the literature.31 The total charge of the system was neutralized by using a homogeneous negative background charge,32,33 and simulations of the global minimum structures were run for over 20 ps to ensure the reliability of the statistics. The bare Al3+-AAA complexes studied previously18 were used as a starting point in the microhydration process, and the hydration reaction of the subsequent hydrated complexes was defined as
[Al-AAA(H2O)n-1]+3 + H2O f [Al-AAA(H2O)n]+3
TABLE 1: Relative Enthalpies and Electronic Energies Arising, Respectively, from the B3LYP/G03 and PBE/CPMD (in Parentheses) Calculations of the Different [Al-Phe-(H2O)n]+3 and [Al-Tyr-(H2O)n]+3 (in Italics) Complexes Studied (in kcal/mol)a zw1 zw1t zw2 cs
n)1
n)2
n)3
n)4
11.2 (5.5) 8.6 (3.1)
0.0 (0.0) 4.7 (0.0)
0.0 (5.0) 1.3 (0.0)
2.7 (4.4) 0.0 (5.5) 2.9 (7.4) 4.9 (7.2)
0.5 (0.0) 0.0 (5.0) 13.5 (13.5) 12.5 (14.8) 8.0 (10.1) 11.5 (14.8) 10.2
0.0 (2.6) 3.2 (0.0) 0.0 (6.1) 1.4 (0.0) 7.6 (1.0) 12.8 (20.8) 18.9 (14.0) 15.6 (17.7)
9.7 (2.35) 7.6 (4.8) 0.0 (0.0) 0.0 (0.0)
cst 2.5 cst(2)
a t denotes a proton transfer from one of the water molecules attached to the metal.
TABLE 2: Relative Enthalpies and Electronic Energies Arising, Respectively, from the B3LYP/G03 and PBE/CPMD (in Parentheses) Calculations of the Different [Al-Trp-(H2O)n]+3 Complexes Studied (in kcal/mol)a zw1-6 zw2-6 zw2-5 cs6 cs6t cs5 cs5t
n)1
n)2
n)3
18.5 (13.4) 8.9 (0.0) 17.1 0.0 (1.3)
0.0 (0.4) 1.7 (0.0) 15.3 6.7
0.0 (0.0) 9.5 (3.4) 18.2
12.1 (13.8)
20.0
n)4 0.0 (0.0) 19.5
8.2
(9.7)
(14.0)
a
(1)
t denotes a proton transfer from one of the water molecules attached to the metal.
with n ) 1-4 being the number of water molecules attached to the metal. These formation free energies, together with the relative stability of the different isomers found upon each water molecule addition, will be studied in the present paper. Results The AAAs have several electron-rich sites to which Al3+ can bind, namely, the aromatic ring and the N and O atoms in the backbone. For a thorough exploration of the potential surface, in the present contribution the cation-π interaction with the aromatic ring, together with the mono- or bicoordination to the AAA backbone, was considered, for both the charge-solvated (cs) and zwitterionic (zw) forms of the AAA. Consequently, a high number of structures was generated, and for the sake of brevity, only the low lying isomers, namely, those within 20 kcal/mol from the global minimum, will be discussed here. Considering the binding mode to the amino acid backbone, three coordination patterns were observed to coexist within the selected energy gap in each step of the microhydration: binding to N and O atoms of the cs AAA (named cs-nw in the present contribution, n being the number of water molecules added) and coordination to one or two of the carboxylic oxygens of the zw form (named zw1-nw and zw2-nw, respectively, n being the number of water molecules added). Trp offers two aromatic rings in the side chain to which the metal can bind, and therefore, the isomers will be named considering whether the sixmembered ring or the five-membered ring is the one interacting with the metal. The gradual filling up of the first solvation shell of the metal results, in some cases, in a spontaneous water or proton migration of the second shell. This structure will be denoted by a t (transfer) added to the name.
Figure 1. Optimized [Al-Phe-(H2O)n]+3 systems (B3LYP/G03 theory level).
As expected,18 the structures found for Tyr and Phe are very similar and therefore will be discussed together, while the Trp complexes will be analyzed separately. Table 1 and Table 2 present relative stabilities for all the hydrated complexes examined, while the corresponding optimized geometries are displayed in Figure 1, Figure 2, and Figure 4. In general, good agreement is found between PBE/CPMD and B3LYP/G03
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Figure 2. Optimized [Al-Trp-(H2O)n]+3 systems (B3LYP/G03 theory level).
calculations, considering the inherent differences of the methods. The occasional discrepancies will be discussed throughout the text, together with the changes the addition of water molecules triggers on some fundamental structural and thermodynamic properties of the complexes. Geometries and Coordination. The coordination of the metal arises from an equilibrium between the charge neutralization of the metal, which tends to saturate the coordination shell of the metal, and the steric hindrance of the structure, which, in turn, has the opposite tendency. The magnitude of these effects arises from the inherent characteristics of the metal, which has a high charge that provides strong bonds, and a small ionic radius, which minimizes the space for the ligands and gives rise to a strong steric hindrance. Consequently, even when the available ligands permit it, Al3+ hexacoordination is not always the most stable coordination pattern, on the contrary to what happens in solution. Even the preferred coordination geometry cannot be definitely assigned, and the global minima at the different hydration levels were found to be tetra- or pentacoordinated, generally at the cost of losing the π coordination or expelling one of the water molecules from the first coordination shell. Phe and Tyr present very similar isomers (see Figure 1 for Phe complexes, and Tyr complexes are available in the Supporting Information; for the sake of brevity and considering the negligible geometrical differences to the PBE/CPMD optimized structures in most of the complexes, only the B3LYP/G03 optimized structures are shown in the pictures), the occasional differences arising from the presence of the -OH group in the aromatic ring of Tyr, which enables hydrogen bonding sites with the water molecules bound to the metal. The three binding modes, namely, cs, zw1, and zw2, are found for n ) 1-4, and both amino acids accept up to four water molecules in the first solvation shell. Regarding the coordination to Trp, the cs, zw1, and zw2 binding modes were found for the different degrees of solvation. The smaller π-electron density at the five-membered ring, arising from the presence of the nitrogen atom, renders the benzene ring of the aromatic face more prone to interact with the metal, as confirmed by the data of Figure 2.18,21 Besides, in the specific
case studied here, the interaction of the Al with the fivemembered ring results in a sterically hindered structure, which destabilizes further the isomer. Consequently, those complexes where the metal interacts with the five-membered ring lie higher in energy, and in fact, no zw1-5 binding mode was found between the low lying isomers with none of the theoretical approximations tried in the present study. Trp complexes also accept up to four water molecules in the coordination shell of the metal but only for the zw structure. In the absence of water molecules, due to the enhanced electrostatic potential arising from the intrinsic properties of the cation, the metal binds very tightly to the ligands.12,13 As water molecules are added, the bond distances between the metal and the O and N atoms of the backbone and water molecules are elongated due to the electron density delocalization from water molecules to the metal, which weaken the binding to the amino acid. The enlargement is most noticeable when the first water molecule is included, while the effect decreases gradually for the further additions, as was already reported in the literature for mono- and bivalent ions.8,13 The complete hydration of the complex results in a bond enlargement of roughly 0.1 Å. On the contrary, the loss of π interaction during the hydration process results in less steric strain but also less charge transfer, and therefore, the bond distance is shortened upon this event (see Supporting Information). Zwitterionic vs Charge-Solvated Conformations. The preference for zw isomers in aqueous solution as opposed to the cs global minima in the gas phase is known in the literature.10 Furthermore, several works have reported the stabilization of zw structures as compared to cs ones upon the gradual addition of water molecules to a bare amino acid and to metal-AA complexes found to present a cs global minimum in the gas phase.6,8,11,12 The number of water molecules required for the conversion can vary between two and six, depending on the metal and the amino acid studied. In the present study, the one-by-one addition of water molecules to the metal bound to the amino acid also has been found to trigger the preference for the zw system. In the gas phase, the cs isomer was preferred, in line with what is expected for small size metals complexing amino acids,3 and the addition
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Figure 3. Hydration free energies of the different [Al-Phe-H2On]+3 (empty symbols), [Al-Tyr-H2On]+3 (filled symbols), and [Al-TrpH2On]+3 (stripped symbols) complexes studied, in kcal/mol.
of the first water molecule does not noticeably alter the stability of the species as compared to the bare Al3+-AAA system, as has been seen to happen for other systems.5,6,8 The cs isomer is still preferred upon the addition of the first water molecule,1 the relative stability of the zw structures being at least 7.6 kcal/ mol higher in the B3LYP/G03 calculations, but much closer in the PBE/CPMD calculations (2.3, 3.1, and -1.3 kcal/mol for Phe, Tyr, and Trp complexes, respectively). As the number of water molecules added is increased, this preference is inverted and for n ) 2, and the zw structures are preferred over the cs ones. Nevertheless, the cs complexes are found close in energy (2.9, 4.9, 6.7, 7.4, and 7.2 kal/mol for B3LYP/G03 and PBE/ CPMD calculations, respectively). Observe that, in general, PBE/ CPMD calculations tend to destabilize the cs conformation with respect to the zw conformation, as compared to the B3LYP/ G03 ones. The difference becomes much larger upon the addition of the third water molecule, now pointing out a clear preference for zw fashion. This pattern is, as expected, enforced as the fourth water molecule is included. The similar relative energies of cs and zw complexes found for the n ) 2, 3 systems suggest that this species could coexist in the gas phase. The interconversion between zw and cs structures of Na+-Val was experimentally seen to be possible for n ) 2;1 regretably, no such kinds of experimental data are available for multiply charged ions or for AAAs. The stability of each global minimum, in this case, was checked at room temperature by means of PBE/CPMD simulations, all of them being found to keep their initial preference for the corresponding cs or zw isomer, during 20 ps. Therefore, the simulations suggest that the interconversion energy between zw and cs complexes is too high for such a conversion to take place and that the presence of the complexes will depend on the experimental setup for the generation of such complexes.8 However, experimental data would be highly desirable for more detailed insight into this issue. Consequently, the unambiguous estimation of the water number required for the stabilization of the zw form is not possible, as already happened with other systems.6,8 Nevertheless, the existence of cs isomers for n ) 4 can be ruled out, based on the high instability of such complexes. Solvation Energies. The hydration reaction as described in eq 1 is a exothermic process, predicting the gradual inclusion of water molecules to be a spontaneous process for [Al-AAA]+3 complexes (see Figure 3). The hydration reaction implies large entropic effects disfavoring the inclusion of one water molecule
Figure 4. Optimized [Al-AAA-(H2O)n]+3 structures showing spontaneous proton and water transfers.
in the shell, estimated to be ∼10 kcal/mol in each addition. To take this effect into account, free energies will be discussed in this section. Both enthalpies and free energies are available in the Supporting Information. As a consequence of the intrinsic size and charge properties of the metal, the stability gained upon the addition of a water molecules is much larger for [Al-AA]+3 complexes than for alkali metal-AA complexes that have been studied in the literature, for which the highest energy gains, those corresponding to the addition of the first and second water molecules, fall in the range of 10-15 kcal/mol, for both Na+ and K+, for different amino acids.1,8,9 The systems chosen here present an affinity of around 70 kcal/mol for the first water molecule. The stepwise addition of a water molecule causes a gradual decrease of the solvation free energies of the complexes, from -70 kcal/ mol for the addition of the first water molecules to -40 kcal/ mol for the third and fourth additions. Similar trends have been observed both theoretically and experimentally for other systems and have been ascribed to the saturation of the coordination shell of the cation, on one hand, and to the neutralization of the charge of the Al3+ by each water added.1 Observe that the less exothermic formation enthalpy occurs when hexa- and pentacoordination are achieved. In previous works,18 the nature of the side chain was seen to influence the affinity of the metal toward the ligands; the more electron donating the ligand, the stronger the binding of the metal. This, in turn, means a looser binding to the added water molecule, as reported in the literature.5 However, no remarkable influence is seen in this case, probably due to the several different factors coming into play in the present complexes, which make the electronic effect of the AAAs difficult to distinguish. Proton Transfer. During the inclusion of water molecules to the systems, spontaneous water migrations to the second hydration shell were observed for the three amino acids (see Figure 4), in particular in Tyr complexes, at both B3LYP/G03 and PBE/CPMD levels of theory (see t complexes in Table 1
Microsolvated Al3+-Aromatic Amino Acid Complexes and Table 2). Although several of them were characterized, only those stabilizing the corresponding fully solvated complex will be discussed here. This feature arose with the inclusion of the third water molecule in Phe and Trp complexes but only for n ) 4 complexes was seen to be more favorable than keeping it bound to the metal. On the contrary, this stabilization was noticed already in n ) 2 complexes for Tyr, probably as a result of the -OH substituent in the Tyr ring, which provides the possibility of forming favorable H-bonds with the water molecules. Among those isomers presenting a water molecule in the second coordination shell, in some cases Al3+ provokes the hydroxylation of one of the water molecules attached in its coordination shell, the released proton interacting with the water molecule in the second hydration shell. Similar proton and water shifts have already been discussed in the literature in other organic Al3+ systems,34–36 ascribing this feature to the polarizing effect of the aluminum ion on the water molecules present in the inner sphere. As previously stated, these phenomena can be explained as a result of the equilibrium between the steric hindrance on the metal’s coordination shell and the favorable charge transfer from the water molecules to the metal. On one hand, the incoming of a water molecule into the inner shell of the metal donates charge to the Al3+, stabilizing the complex, at the cost of increasing its steric hindrance. As more water molecules are added, the steric hindrance becomes too large and the charge on the metal lower, and therefore, expelling a water molecule to the second hydration shell can help the overall stabilization of the complex more than keeping it directly bound to the Al3+. On the other hand, when the charge in the metal is still large enough to polarize the water molecules attached to it, and there is a proton acceptor available, the ejection of a proton out of the inner shell of the metal is likely to happen, resulting in a negatively charged hydroxyl bound to the metal, which stabilizes the structure, neutralizing the charge of the metal. In some of the complexes studied here, the steric hindrance is too high to accept another water molecule in the inner shell, and even the charge in the metal is still too high. The proton shift is the mechanism the metal uses for neutralizing its charge, at the same time that the steric hindrance is lowered. This mechanism results in a rather small stabilization of about 2 kcal/mol, which reflects how subtle the equilibrium between the factors alluded to earlier is in this case. However, it clearly points out that in the competition between the metal hydration and ligation the latter is most favorable. Cation-π Interaction. In the present work, isomers with and without cation-π interactions were considered. Those without interaction with the ring gave rise to open linear structures, while the inclusion of cation-π interactions forced the structure to bend toward the ring, forming closed structures. The study of the bare Al3+-AAA18 systems clearly showed the additional stability gained via the cation-π interaction, which favored closed structures. This stabilization is also present in the microhydrated structures, but as a result of the stepwise addition of the water molecules, the cation-π interaction is gradually weakened, as reflected by the larger distances between the metal and the ring and the smaller charge transfer shown in the NBO analysis (see Supporting Information), where secondorder interactions are mantained in the B3LYP/G03 calculations, stabilizing the overall structure. The presence of the cation-π interactions during the microhydrated process is seen to depend on the binding mode of the metal. For cs and zw1 structures, the open structures are found
J. Phys. Chem. B, Vol. 114, No. 27, 2010 9021 more than 20 kcal/mol higher than the global minimum, mantaining the interaction for the fully solvated structures and overcoming the opposing distortion energy. Instead, open zw2 structures are predicted to lie within 20 kcal/mol, for n ) 2 in Phe. From n ) 3 on, the gap between open and closed complexes becomes smaller for Phe and Tyr, and zw2 open structures are considered more stable, even if within a few kilocalories/mole. The gap between the open and closed structures is larger in dynamics calculations, which, in fact, predict the Trp to show the same behavior, while B3LYP/G03 calculations, even if located in the open zw2 complex within 20 kcal/mol for n ) 3, favor the closed formation (see Supporting Information). The bond to two oxygen atoms in the zw2 complexes supposes a larger charge transfer than the other binding mode. Therefore, when the hydration degree is high enough, the additional stabilization gained via the cation-π interaction does not compensate the steric hindrance payed in closed structures. These discrepancies point out that the cation-π interaction is more labile as the water molecules are added and that it does not provide a strong stabilization of the overall complex when the metal is bound to strong electron-donating atoms. Nevertheless, the data supports the existence of such interactions in hydrated environments for the low lying isomers, in line with the results of the PBE/CPMD calculations on Na+-Phe complexes in solution,10,37 who predicted the cation-π interaction to be present even in the aqueous solution, for the zw1 binding mode. Conclusions The microhydrated environment promotes the stabilization of some conformers which are less populated in the absence of water molecules, in particular, the zw2 binding mode in Trp complexes and, in general, the zw structures of all the amino acids. Moreover, the latter is predicted to coexist with the cs structures already when two water molecules are bound to the metal and is the most stable conformer when the fourth water molecule is added. This feature is widely known to happen in bulk solvent, but in fact, this study points out that it is rather related to the change in the metal’s properties, as the zw form is seen to be preferred already in the gas phase upon the attachment of bigger cations. Al3+ retains the coordination pattern seen in the bare + Al -AAA systems, in line with its hard metal nature, preferring the harder O binding sites to the softer N ones. The metal accepts up to four water molecules in its shell, the attachment of the first and the second being especially exothermic and, therefore, highly stabilizing the complex. At this point the metal is rather saturated, and the addition of new water molecules, even if exothermic, does not suppose such a big energy gain anymore. This hydration results in an alteration of structural and thermochemical properties, which have been seen to be dominated by the charge neutralization of the metal and the overall steric hindrance of the complex: the coordination mode, the degree of hydration of the metal, and solvation energies are the result of a subtle equilibrium between these forces, enhanced by the high charge and small size of the metal. Instead, the main features are not remarkably influenced by the different side chains considered, whose effect is attenuated as compared to the nonhydrated complexes. As reflected by the migration of waters to the second solvation shell, the metal-ligation is preferred to metal-hydration. In fact, when the metal is fully solvated, it prefers to adopt a penta- or tetracoordinated binding fashion (lower coordination number
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than that found in aqueous environment) to minimize the steric hindrance by losing water interactions and maintaining the interaction with the ligands. The attachment of water molecules, furthermore, leads to a weaker cation-π interaction; nevertheless, in most of the cases, it is strong enough to overcome the steric hindrance arising from such a closed structure, maintaining such a conformation even in the most solvent exposed situations. Acknowledgment. This research was funded by Euskal Herriko Unibertsitatea (the University of the Basque Country), Gipuzkoako Foru Aldundia (the Provincial Government of Gipuzkoa), and Eusko Jaurlaritza (the Basque Government). The SGI/IZO-SGIker UPV/EHU (supported by the National Program for the Promotion of the Human Resources within the National Plan of Scientific Research, Development and Innovation, Fondo Social Europeo and MCyT) is gratefully acknowledged for assistance and generous allocation of computational resources, together with the Universit’a degli Studi della Calabria and MIUR (PRIN 2008). Supporting Information Available: Additional Tables 1-12 and Figures 1 and 2. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Wincel, H. J. Phys. Chem. A 2007, 111, 5784. (2) Zatta, P.; Lucchini, R.; van Rensburg, S.; Taylor, A. Brain Res. Bull. 2003, 62, 15. (3) Jockusch, R.; Lemoff, A. S.; Williams, E. R. J. Am. Chem. Soc. 2001, 123, 12255. (4) Kamariotis, A.; Boyarkin, O. V.; Mercier, S. R.; Beck, R. D.; Bush, M. F.; Williams, E. R.; Rizzo, T. R. J. Am. Chem. Soc. 2006, 128, 905. (5) Lemoff, A. S.; Bush, M. F.; Wu, C.; Williams, E. R. J. Am. Chem. Soc. 2005, 127, 10276. (6) Lemoff, A. S.; Williams, E. R. J. Am. Soc. Mass Spectrom. 2004, 15, 1014. (7) Lemoff, A. S.; Wu, C.; Bush, M. F.; Williams, E. R. J. Phys. Chem. A 2006, 110, 3662. (8) Ye, S. J.; Moision, R. M.; Armentrout, P. B. Int. J. Mass Spectrom. 2005, 240, 233. (9) Wincel, H. Am. Soc. Mass Spectrom. 2007, 18, 2083. (10) Costanzo, F.; Valle, R. G.; Barone, V. J. Phys. Chem. B 2005, 109, 23016. (11) Remko, M.; Rode, B. M. J. Phys. Chem. A 2006, 110, 1960. (12) Ai, H.; Bu, Y.; Han, K. J. Chem. Phys. 2003, 118, 10973. (13) Marino, T.; Toscano, M.; Russo, N.; Grand, A. J. Phys. Chem. B 2006, 110, 24666. (14) Dougherty, D. A. Science 1996, 271, 163.
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