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ABSTRACT: The mechanism of amino acid transfer across water/hydrophobic interfaces has important biological relevance but is poorly understood. Combined QM/MM simulations show that zwitterionic Gly enters the hydrophobic phase till ca. 1 nm before neutralisation occurs. Interfacial effects significantly affect the relative tautomers stability.
Physical Chemistry Chemical Physics 06/2011; 13(24):11579-82. · 3.57 Impact Factor
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ABSTRACT: We report a study on different ionization states and conformations of the bimolecular (Gly)(2) system by means of quantum mechanical calculations. Optimized geometries for energy minima of the glycine dimer, as well as relative energies and free energies were computed as a function of the medium: gas phase, nonpolar polarizable solvent, and aqueous solution. The polarizable continuum model was employed to account for solvation effects. Energy calculations were done using the MP2/aug-cc-pVTZ and B3LYP/6-311+G(2df,2p) methods on B3LYP/6-31+G(d,p) optimized structures (some single-point energy calculations were also done using the B3PW91 and PBE1KCIS methods). Ionized forms of the glycine dimer (either zwitterion-zwitterion or neutral-zwitterion) are predicted to exist in all media, in contrast to amino acid monomers. In aqueous solution, dimerization is an exergonic process (-4 kcal mol(-1)). Thus, according to our results, zwitterion-zwitterion Gly dimers might be abundant in supersaturated glycine aqueous solutions, a fact that has been connected with the structure of α-glycine crystals but that remains controversial in the literature. Another noticeable result is that zwitterion-zwitterion interactions are substantially underestimated when computed using methods based on density functional theory. For comparison, some calculations for the dimer of the simplest chiral amino acid alanine were done as well and differences to the glycine dimer are discussed.
ChemPhysChem 11/2010; 11(16):3499-504. · 3.41 Impact Factor
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ABSTRACT: Cyclodextrins have attracted much interest in recent years because of their potential use as molecular reactors allowing organic reactions in aqueous solution. To better understand their effect on reaction mechanisms, we have carried out a computational study of a prototypical process (neutral ester hydrolysis) in a beta-cyclodextrin (beta-CD). Two models have been used for the reactor. The first and simpler one assumes that the medium can be described by a polarizable dielectric continuum. The second one takes into account the discrete nature of the beta-CD and water molecules thanks to a computational approach that combines the use of Quantum Mechanics, Molecular Mechanics and Molecular Dynamics techniques. We focus on neutral pH processes for which either acceleration or inhibition has experimentally been observed depending on ester derivatives. Our calculations rationalize such observations by showing that the two reaction mechanisms usually invoked for hydrolysis, stepwise (involving two transitions states with formation of a -C(OH)(2)OR tetrahedral intermediate) and concerted, undergo opposite effects in the beta-CD environment. The results highlight the role played by molecular shape recognition. Thus, in spite of a higher polarity exhibited by the three transition states with respect to the reactants, the interactions with the beta-CD cavity may either increase or decrease the activation barrier due to different 3D-arrangements of the chemical structures.
Organic & Biomolecular Chemistry 10/2010; 8(19):4346-55. · 3.70 Impact Factor
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ABSTRACT: We describe an efficient and accurate method to compute free energy changes in complex chemical systems that cannot be described through classical molecular dynamics simulations, examples of which are chemical and photochemical reactions in solution, enzymes, interfaces, etc. It is based on the use of dual-level Born-Oppenheimer molecular dynamics simulations. A low-level quantum mechanical method is employed to calculate the potential of mean force through the umbrella sampling technique. Then, a high-level quantum mechanical method is used to estimate a free energy correction on selected points of the reaction coordinate using perturbation theory. The precision of the results is comparable to that of ab initio molecular dynamics methods such as the Car-Parrinello approach but the computational cost is much lower, roughly by two to three orders of magnitude. The method is illustrated by discussing the association free energy of simple organometallic compounds, although the field of application is very broad.
The Journal of chemical physics 08/2010; 133(6):064103. · 3.09 Impact Factor
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ABSTRACT: The reactivity of alkyllithium-lithium-aminoalkoxide unimetallic superbases has been investigated. These systems are used for deprotonative lithiation of pyridine derivatives in apolar non-coordinating media with excellent regio- and chemoselectivity, in deep contrast with alkyllithium. With the aim of getting a better understanding of the chemistry behind these promising reagents, we have carried out a joint experimental and theoretical study of the metalation of 2-chloropyridine with combinations of nBuLi and (S)-(-)-N-methyl-2-pyrrolidinylmethoxide (LiPM). Nucleophilic addition or alpha-lithiation has been observed, depending on conditions (solvent, temperature, stoichiometry), while ortho-metalation was not detected. Theoretical calculations using Density Functional Theory (B3LYP/6-31G(d) method) have then been carried out in gas phase at 195 K to characterize the relevant chemical species (reactive aggregates, transition structures) and estimate free energies of activation and relative reaction rates. Solvent effects in hexane have been neglected according to previous calculations. The effect of coordinating solvents such as THF has been qualitatively discussed. A major achievement of the present work has been to demonstrate that chemoselectivity crucially depends on aggregate type: dimers systematically lead to nucleophilic addition, while tetramers lead to alpha-lithiation. Besides, the calculations predict dimers to be more reactive than tetramers, yet they are much less stable, so that the observed selectivity results from the combination of both properties. A simple procedure to evaluate the basicity of an organlithium compound has been proposed. It has allowed us to show that the nBuLi-LiPM tetramer has a significantly larger basicity than its corresponding dimer, which is not at all the case for nBuLi aggregates, thus explaining differences in selectivity. Solvent and temperature effects on nBuLi-LiPM reactivity have been analyzed. By increasing the temperature in hexane, or changing the solvent from hexane to THF, dimer concentration is expected to rise, and likewise the weight of nucleophilic addition rises, in agreement with the experimental findings.
Journal of the American Chemical Society 02/2010; 132(7):2410-6. · 9.91 Impact Factor
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ABSTRACT: Mixed alkyllithium/lithium alkoxides aggregates are important species in synthetic organic chemistry, but their electronic and geometric properties have not been extensively studied yet. The main objective of this work was to analyze the structure of simple prototypical aggregates in a coordinating solvent with the help of elaborated theoretical chemistry calculations. Within this aim, we have carried out molecular dynamics simulations for MeOLi, (EtLi)(MeOLi), and (EtLi)(2)(MeOLi)(2) systems in dimethyl ether solution. We use a combined QM/MM (quantum mechanics/molecular mechanics) force field that allows an appropriate description of the aggregate structure and of its interactions with the solvent. In the simulations, the aggregates are described at the B3LYP/6-31G(d) level while the solvent is described using the classical OPLS potential. For completeness, the influence of the chemical environment on the C-O-Li bond structure has been analyzed in some detail. The discussion focuses on (1) the distinctive properties of the alkoxide C-O-Li bond pattern, (2) the coordination of solvent molecules to the aggregates (number, stability), and (3) the time fluctuations of main structural parameters (Li-C and Li-O distances). We also show that nonclassical C-H...O hydrogen bonds involving H atoms of the solvent methyl groups and the O atom of the alkoxide are formed in the solvated MeOLi monomer and (EtLi)(MeOLi) dimer. Owing to these specific interactions, the monomer exhibits a nonlinear C-O-Li bond in solution.
The Journal of Physical Chemistry B 05/2009; 113(18):6459-67. · 3.70 Impact Factor
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ABSTRACT: Quantum chemical calculations are reported to provide new insights on plausible mechanisms leading to the deamidation of asparagine residues in proteins and peptides. Direct hydrolysis to aspartic acid and several succinimide-mediated mechanisms have been described. The catalytic effect of water molecules has been explicitly analyzed. Calculations have been carried out at the density functional level (B3LYP/6-31+G**). Comparisons of free energy profiles show that the most favorable reaction mechanism goes through formation of a succinimide intermediate and involves tautomerization of the asparagine amide to the corresponding imidic acid as the initial reaction step. Another striking result is that direct water-assisted hydrolysis is competitive with the succinimide-mediated deamidation routes even in the absence of acid or base catalysis. The rate-determining step for the formation of the succinimide intermediate is cyclization, regardless of the mechanism. The rate-determining step for the complete deamidation is the hydrolysis of the succinimide intermediate. These results allow clarification of some well-known facts, such as the isolation of succinimide or the absence of iso-Asp among the reaction products observed in some experiments.
The Journal of Physical Chemistry A 02/2009; 113(6):1111-20. · 2.95 Impact Factor
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ABSTRACT: Molecular dynamics simulations of organolithium aggregates in solution are reported for the first time. We use a combined
quantum/classical force field (the so-called QM/MM approach) and study ethyl-lithium aggregates in dimethyl ether (DME) solvent.
The solutes are described at the Density Functional Theory level while solvent molecules are described using molecular mechanics.
NVT Molecular Dynamics simulations at 200 K are carried out in the Born–Oppenheimer approximation. After equilibration, the
production phase was run for 80 ps (monomer), 40 ps (dimer) and 26 ps (tetramer). The analysis of the results focuses on Li
coordination as a function of aggregate size and we show that the total Li coordination number is always 4. No decoordination
has been observed along the simulations. Fluctuations of the structures are predicted to be large in some cases and possible
implications on reactivity are discussed.
Theoretical Chemistry Accounts 11/2008; 121(5):321-326. · 2.16 Impact Factor
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ABSTRACT: alpha-Aminophosphonic acids are analogues of natural alpha-aminoacids and very promising agents for use in various pharmaceutical applications. However, in contrast to the numerous theoretical investigations on the structure of natural alpha-aminoacids, only very few studies on alpha-aminophosphonic acids have been performed. In the present work, we report a detailed investigation of the simplest compound, the glycine analogue aminomethylphosphonic acid (AMPA), by means of quantum mechanical calculations at the B3LYP/6-311++G(3df,2p)//B3LYP/6-31+G(d,p) and MP2/6-311++G(3df,2p)//B3LYP/6-31+G(d,p) levels. We focus on the structure of the neutral species looking at the evolution of non-ionized and ionized forms from gas phase to non-polar solvents and aqueous media. Continuum and discrete-continuum solvent models have been employed to account for the effects of the environment. The discussion is centered on: (1) the geometry and relative stability of possible conformers in gas phase and aqueous solution, (2) the free energy of tautomerization in different media, (3) the role of hydrogen bonds in liquid water, and (4) the free energy of transfer from water to a hydrophobic solvent such as cyclohexane. Systematic comparison between AMPA and Gly is performed. Though both systems exhibit many similarities, some important differences have also been found that may be explained, at least in part, by the higher acidity of phosphonic acids compared to carboxylic acids. In particular, in solvents lacking hydrogen-bond formation capability, Gly derivatives should mainly exist as non-ionized molecules while the equivalent AMPA derivatives should adopt a zwitterionic structure in media with dielectric constant above 10. This might have significant environmental or biological consequences that will need to be addressed.
Physical Chemistry Chemical Physics 10/2008; 10(36):5624-32. · 3.57 Impact Factor
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ABSTRACT: The HO(3) and HO(4) polyoxide radicals have attracted some attention due to their potential role in ozone chemistry. Experimentally, the geometrical structure of HO(3) is known whereas that of HO(4) is not. Moreover, the existence of the latter radical has been questioned. Theoretical calculations on the two species have been reported before, showing important structural differences depending on the computational level. Both radicals present an unusually long OO bond (around 1.7-1.8 A) that can be associated with an intricate interaction between HO, or HO(2), with O(2). The nature of such interaction is investigated in detail using large scale ab initio methods (CASSCF, CASPT2, MRCI, QCISD, CCSD(T)) and density functional techniques (B3LYP) in connection with extended basis sets. Stabilization enthalpies at 298 K with respect to HO (or HO(2)) and O(2) have been computed amounting to -3.21 kcal mol(-1) for HO(3) (trans conformation) and 11.33 kcal mol(-1) for HO(4) (cis conformation). The corresponding formation enthalpies are 6.12 and 11.83 kcal mol(-1). The trans conformation of HO(4) is less stable than the cis one by 6.17 kcal mol(-1). Transition states for HO(4) dissociation and for cis/trans conversion are also described.
Physical Chemistry Chemical Physics 12/2007; 9(44):5865-73. · 3.57 Impact Factor
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ABSTRACT: Deamidation of proteins occurs spontaneously under physiological conditions. Asparaginyl (Asn) residues may deamidate into aspartyl (Asp) residues, causing a change in both the charge and the conformation of peptides. It has been previously proposed by Capasso et al. that deamidation of relatively unrestrained Asn residues proceeds through a succinimide intermediate. This mechanism has been modeled by Konuklar et al. and the rate determining step for the deamidation process in neutral media has been shown to be the cyclization step leading to the succinimide intermediate. In the present study, possible water-assisted mechanisms, for both concerted and stepwise succinimide formation, were computationally explored using the B3LYP method with 6-31+G* basis set. Single point solvent calculations were carried out in water, by means of integral equation formalism-polarizable continuum model (IEF-PCM) at the B3LYP/6-31++G* level of theory. A novel route leading to the succinimide intermediate via tautomerization of the Asn side chain amide functionality has been proposed. The energetics of these pathways have been subject to a comparative study to identify the most probable mechanism for the deamidation of peptides in solution.
The Journal of Physical Chemistry A 08/2006; 110(27):8354-65. · 2.95 Impact Factor
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ABSTRACT: Ozone in aqueous solution decomposes through a complex mechanism that involves initial reaction with a hydroxide ion followed by formation of a variety of oxidizing species such as HO, HO(2), and HO(3) radicals. Though a number of hydrogen-bonded complexes have been described in the gas phase, both theoretically and experimentally, the structures of ozone and HO(x) in liquid water remain uncertain. In this work, combined quantum/classical computer simulations of aqueous solutions of these species have been reported. The results show that ozone undergoes noticeable electron polarization but it does not participate in hydrogen bonds with liquid water. The main contribution of the solvation energy comes from dispersion forces. In contrast, HO(x) radicals form strong hydrogen bonds. They are better proton donors but weaker proton acceptors than water. Their electronic and geometrical structures are significantly modified by the solvent, especially in the case of HO(3). In all cases, fluctuations in amplitudes of electronic properties are considerable, suggesting that solvent effects might play a crucial role on oxidation mechanisms initiated by ozone in liquid water. These mechanisms are important in a broad range of domains, such as atmospheric processes, plant response to ambient ozone, and medical and industrial applications.
The Journal of Chemical Physics 06/2006; 124(19):194502. · 3.33 Impact Factor
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ABSTRACT: The HOOO radical is supposed to play a role in ozone chemistry, both in the gas phase and aqueous media. We discuss the influence of the solvent on the electronic and geometrical structure of this radical using density functional and high-level ab initio calculations together with continuum, discrete, and discrete-continuum solvent models. Solute-solvent electrostatic interactions are shown to be fundamental, and lead to a noticeable stabilization of the radical, which should adopt a trans conformation in aqueous media. In fact, no energy minimum for the cis conformation is predicted in these conditions.
ChemPhysChem 03/2006; 7(2):463-7. · 3.41 Impact Factor
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ABSTRACT: The neutral hydrolysis of formamide in water is a suitable reference to quantify the efficiency of proteolytic enzymes. However, experimental data for this reaction has only very recently been obtained and the kinetic constant determined experimentally is significantly higher than that predicted by previous theoretical estimations. In this work, we have investigated in detail the possible mechanisms of this reaction. Several solvent models have been considered that represent a considerable improvement on those used in previous studies. Density functional and ab initio calculations have been carried out on a system which explicitly includes the first solvation shell of the formamide molecule. Its interaction with the bulk has been treated with the aid of a dielectric continuum model. Molecular dynamics simulations at the combined density functional/molecular mechanics level have been carried out in parallel to better understand the structure of the reaction intermediates in aqueous solution. Overall, the most favored mechanism predicted by our study involves two reaction steps. In the first step, the carbonyl group of the formamide molecule is hydrated to form a diol intermediate. The corresponding transition structure involves two water molecules. From this intermediate, a water-assisted proton transfer occurs from one of the hydroxy groups to the amino group. This reaction step may lead either to the formation of a new reaction intermediate with a marked zwitterionic character or to dissociation of the system into ammonia and formic acid. The zwitterionic intermediate dissociates quite easily but its lifetime is not negligible and it could play a role in the hydrolysis of substituted amides or peptides. The predicted pseudo-first-order kinetic constant for the rate-limiting step (the first step) of the hydrolysis reaction at 25 degrees C (3.9x10(-10) s(-1)) is in excellent agreement with experimental data (1.1x10(-10) s(-1)).
Chemistry 12/2005; 11(22):6743-53. · 5.93 Impact Factor
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ABSTRACT: We present an analysis of rare event trajectories for the nucleophilic displacement of a chloride anion of 1,2-dichloroethane by a carboxylate group in haloalkane dehalogenase from Xanthobacterautotrophicus (DhlA) and in aqueous solution. Differences in the transmission coefficient are rationalized on the basis of the electrostatic coupling between the chemical system and the environment. Detailed analysis of the reactive trajectories reveals that the evolution of the hydrogen bond interactions established between the substrate and the environment present significant differences in aqueous solution and in the enzyme. The structure of the enzymatic active site provides a more adequate interaction pattern for the reaction progress.
Journal of the American Chemical Society 03/2005; 127(6):1946-57. · 9.91 Impact Factor
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ABSTRACT: A density functional study has been performed on Rb(+) and Cs(+) complexes of mono and tribenzo derivatives of the 21Crown7 crown ether. Calculations have been carried out using the B3LYP functional together with a split valence basis set with additional polarization and diffuse functions. The cations have been described with effective core potentials. Structures of the tribenzo-21Crown7 are compared to X-ray data. The Rb(+)/Cs(+) affinity of the benzo and tribenzo derivatives in gas phase is discussed on the basis of binding energies, strain energies, and electrostatic contributions. For the first time, a detailed description of the effect arising from the presence of benzo groups is described. On one hand, the benzo groups decrease the electronic density on the ether oxygen atoms. On the other hand, they confer a stronger electronic polarizability to the ligand. The energetic analysis shows that the polarization contributions play a crucial role and reach up to 29% of the total electrostatic energy.
Journal of Computational Chemistry 06/2002; 23(7):724-31. · 4.58 Impact Factor
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ABSTRACT: The reaction field of a water molecule in liquid water has been computed with the help of continuum, discrete-continuum, and discrete models, using density functional theory calculations. In the continuum model, the liquid is simply described by a polarizable dielectric medium. The solute is placed in a cavity defined by a scaled van der Waals surface. Two different sets of van der Waals radii have been used for the atomic spheres. The discrete-continuum model consists of a quantum molecule surrounded by four classical molecules, the resulting aggregate being embedded in a dielectric continuum. Finally, in the discrete model, a molecular dynamics simulation is carried out for a quantum molecule in a box containing 215 classical molecules with periodic boundary conditions. The reaction field and the induced dipole moment in the standard continuum model are substantially underestimated. However, the use of optimized van der Waals radii for the atomic spheres produces a notable improvement. The discrete-continuum and discrete models lead to close results that are in good agreement with experimental data and previous theoretical estimations. For instance, the induced dipole moment (0.80 and 0.82 D for discrete-continuum and discrete models, respectively) compares well with the experimental estimate (0.75 D) and with Car–Parrinello simulations (1.08 D). The reaction field potential is analyzed in terms of multipole moment contributions. The role of the first shell and bulk solvent are also examined. © 2001 American Institute of Physics.
The Journal of Chemical Physics 09/2001; 115(11):5220-5227. · 3.33 Impact Factor
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ABSTRACT: Serine amino acid in aqueous solution is theoretically studied at the B3PW91/6-31+G** level using a dielectric continuum solvent model. Neutral and zwitterionic structures in the gas phase and in solution are
described and the proton-transfer mechanism is discussed. A neutral conformation in which the carboxyl hydrogen atom is already
oriented toward the amino group seems to be the absolute energy minimum in the gas phase and the most stable neutral form
in solution. The absolute energy minimum in solution is a zwitterionic form. The energy barrier for proton transfer is predicted
to be very small, in particular when zero-point-energy contributions are added. Our calculations allow the dynamic aspects
of the ionization mechanism to be discussed by incorporating nonequilibrium effects.
Theoretical Chemistry Accounts 05/2000; 104(2):89-95. · 2.16 Impact Factor
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ABSTRACT: Hydrogen bonding is not well described by available semiempirical theories. This is an important restriction because hydrogen bonds represent a key feature in many chemical and biochemical processes, besides being responsible for the singular properties of water. In this study, we describe a possible solution to this problem. The basic idea is to replace the nonphysical gaussian correction functions (GCF) appearing in the core–core repulsion terms of most MNDO-based semiempirical methods by a simple function exhibiting the correct physical behavior in the whole range of intermolecular separation distances. The parameterized interaction function (PIF) is the sum of atom-pair contributions, each one having five adjustable parameters. In this work, the approach is used to study water–water interactions. The parameters are optimized to reproduce a reference ab initio intermolecular energy surface for the water–water dimer obtained at the MP2/aug-cc-pVQZ level. OO, OH, and HH parameters are reported for the PM3 method. The results of PM3-PIF calculations remarkably improve qualitatively and quantitatively those obtained at the standard PM3 level, both for water–dimer properties and for water clusters up to the hexamer. For example, the root-mean-square deviation of the PM3-PIF interaction energies, with respect to ab initio values obtained using 700 points of the water dimer surface, is only 0.47 kcal/mol. This value is much smaller than that obtained using the standard PM3 method (4.2 kcal/mol). The PM3-PIF water dimer energy minimum (−5.0 kcal/mol) is also much closer to ab initio data (−5.0±0.01 kcal/mol) than PM3 (−3.50 kcal/mol). The method is therefore promising for the development of new semiempirical approaches as well as for application of combined quantum mechanics and molecular mechanics techniques to investigate chemical processes in water. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 572–581, 2000
Journal of Computational Chemistry 01/2000; 21:572-581. · 4.58 Impact Factor
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ABSTRACT: In this article, we analyze the results of a molecular dynamics simulation in aqueous solution of the N-methylazetidinone molecule, often used to model β-lactam antibiotics. The radial distribution functions (RDFs) corresponding to the most interesting atoms, in terms of reactivity,
are presented. We focus our study on the effect of a polar environment on the molecule. The solvent structure around the system
is compared to the structure of β-lactam-water complexes, as obtained in a previous study of reaction mechanisms for the neutral and alkaline hydrolyses of
N-methylazetidinone. Two types of complexes have been considered which are related to different hydrolysis mechanisms having
similar energy barriers at the rate-limiting step of the reaction path. In the first type, the β-lactam-water interaction takes place through the oxygen carbonyl atom and there is agreement between the maxima of the RDFs
obtained here and the ab initio structure of the complexes previously reported. In the second type, the interaction takes
place through the nitrogen atom and we do not predict a coordination layer around the β-lactam nitrogen atom. The results suggest that in aqueous solution hydrolysis of the carbonyl group is the most probable
starting point for the overall hydrolysis reaction. Some discussion on the use of cluster models to represent the solvent
effect is included.
Theoretical Chemistry Accounts 01/1999; 101(5):336-342. · 2.16 Impact Factor
