Giuliano Alagona

An appraisal of solvation effects on chemical functional groups: The amidic and the esteric linkages

Abstract The effect of the solvent on some specific properties of two solutes, N -methylformamide ( 1 ) and methylformate ( 2 ), was examined making use of a continuous model for solutions in an ab initio quantum-mechanical formulation. The analysis regards energetic quantities as well as other observables. An estimate of the different contributions for the energy is given, including also the thermal contributions (due to vibrations, rotations and hindered motions inside the solution) for several geometrical configurations of 1 and 2 : the stable cis and trans conformations, and the transition states for internal conversion. An estimate of this kind, based on ab initio calculations, was done here for the first time. Among the properties taken into consideration we quote the results of geometry optimization in solution (for stable as well as for transient conformations), performed with an automated program employed here for the first time. The analysis is extended to solvent effects on the MO energies, on the dipole moment, on the rotational barrier for the CH 3 group (at different conformations), on the atomic populations and bond indexes. An interpretation of all the above-mentioned solvent effects is given. The interpretation is intuitively satisfactory and supported by quantitative correlations of good quality, making use of simple semiclassical concepts, of general applicability, and of the corresponding numerical information derived from the ab initio calculations. The influence of the basis set, ranging from the STO-3G basis set to the 6-31G ∗ one, was also examined.

Monte Carlo simulation studies of the solvation of ions. 2. Glycine zwitterion

Abstract A Monte Carlo (MC) simulation has been carried out on the zwitterionic form of glycine in water, using TIP4P potentials for water and analogous potentials for the solute. In the conformation considered an intramolecular H bond between one of the carboxyl oxygens and one of the ammonium hydrogens is present, that prevents an intermolecular H bond with solvent for both atoms. As in the case of the solvation of the individual ions, analysis of the water structure around the solute suggests four types of water: (a) those tightly bound to the oxygens of the carboxyl group; (b) those tightly bound to the hydrogens of the ammonium group; (c) hydrophobically bound waters near the methylene group and (d) bulk waters. An enthalpy of solvation of −70 kcal/mol is calculated, in reasonable agreement with the experimental value.

Theoretical Investigation of Tautomeric Equilibria for Isonicotinic Acid, 4-Pyridone, and Acetylacetone in Vacuo and in Solution.

Tautomeric equilibria have been theoretically calculated for isonicotinic acid (neutral and zwitterionic forms), the 4-pyridone/4-hydroxypyridine system, and the keto-enol transformation for acetylacetone in vacuo and in tetrahydrofuran, methanol, and water solvents. Solvent, basis set, and cavity model effects have been studied in the integral equation formalism for the polarizable continuum model (IEF-PCM)/B3LYP framework, as well as the effect of the procedure, CHELPG or RESP, applied in fitting atomic charges to the in-solution molecular electrostatic potential (ELPO). The in-solution optimized geometries obtained at the IEF-PCM/B3LYP/6-31G* and 6-311++G** levels differ moderately but deviate from their gas-phase counterparts. Atomic charges fitted to the in-solution ELPO show small variations in the considered solvents, as well as when the united-atom cavity model, or a model with explicit consideration of polar hydrogens and scaled Bondi radii, has been applied. In contrast, the fitting procedure considerably affects the derived charges producing more separated atomic charges when the CHELPG rather than the RESP procedure is utilized. The fitted charges increase up to 20% in absolute value when the basis set is enlarged from 6-31G* to 6-311++G** in the IEF-PCM/B3LYP calculations. The relative free energy, calculated as ΔGtot = ΔEint + ΔG(solv) + ΔGthermal + (symmetry correction), in an ab initio/density funtional theory (DFT) + free energy perturbation (FEP)/Monte Carlo (MC) approximation strongly depends on the accepted value for the relative internal energy, ΔEint, of the tautomers. ΔEint is to be calculated at the IEF-PCM/QCISD(T)/cc-pVTZ//IEF-PCM/B3LYP/6-31G* level for the isonicotinic acid tautomers for producing relative free energies in aqueous solution close to experimental values. In other solvents, for this system and for the other two tautomeric equilibria, calculation of ΔEint at the IEF-PCM/B3LYP/6-31G* level produces ΔGtot in agreement up to 1 kcal/mol with the experimental values. FEP/MC ΔG(solv) calculations provide robust results with RESP charges derived by a fit to the in-solution ELPO generated at the IEF-PCM/B3LYP/6-31G* level. Molecular dynamics simulations pointed out that isonicotinic acid forms a dimeric zwitterion in tetrahydrofuran, in contrast to what happens in aqueous solution, and this structural peculiarity was interpreted as the reason for the failure of the ab initio/DFT + FEP/MC method in this particular solution.

The influence of the basis set on the evaluation of conformational energies for small organic solutes in aqueous solutions

Abstract Conformational energies of a small set of double rotor molecules (CH 3 CH 2 OH, CH 3 CHFOH(S), CH 2 FCH 2 OH, NH 2 CH 2 OH, CH 3 CH 2 OF) computed in vacuo and in aqueous solution with three basis sets (STO-3G, 3-21G, 4-31G) are compared in order to examine the basis set dependence of the results. Solvent effects are introduced with an SCF algorithm which relies on a continuum description of the solvent. The interaction operator depends on the description of the solute charge distribution and, consequently, on the basis set employed in the calculations.

Semiclassical models in theoretical chemistry. Some results and future prospects

Abstract We present and justify the use of a set of related semiclassical models in the interpretation and prediction of a wide variety of molecular interaction phenomena. The semiclassical model uses ab initio quantum mechanical descriptions of the charge distribution of molecular subunits, interacting according to classical rules. The considered interaction phenomena mainly regard chemical processes (formation of bound aggregates, disruption and formation of covalent bonds) viewed under the energetic as well as the structural point of view, and solvent effects on the solute properties (conformation, reactivity, expectation value of physical observables), as examples of a more general interpretation scheme. Attention is paid to the transferability properties of subunits, and to the description of non-linear effects induced by the specific field acting on these subunits in the various situations. The paper summarizes results obtained in the preceding years, with the addition of fresh numerical data referred to the 3-21G basis set, and presents some new applications among which we signal a simplified procedure to compute the electrostatic contribution to the solvation free energy.

Simple model for the effect of Glu165 → Asp165 mutation on the rate of catalysis in triose phosphate isomerase☆

We present an ab-initio self-consistent field calculation with a 4-31G basis set on a simple model for proton abstraction from hydroxyacetone (a model for dihydroxyacetone phosphate; DHAP) by formate, which is a model for Glu165 in triose phosphate isomerase. Earlier, we showed that the electrophilic groups on the enzyme (the NH3+ of Lys13 and the NH of His95) were essential to efficient catalysis by triose phosphate isomerase. These groups stabilized the enediolate formed by proton abstraction from the DHAP model so that proton transfer from this molecule to Glu165 became likely. In this study, we carry this analysis one step further. First, we re-examine the energy profile for proton transfer, using the fact that our earlier calculations showed that the combined effect of His95 and Lys13 on the reactant DHAP and intermediate enediolate was to make them equal in energy. Then, we analyze the likely effect of changing Glu165 to Asp165 and relate this to experiments on the kinetics of enzyme catalysis by the Glu165----Asp165 mutant.

Towards a unified view of the description of internal and external fields acting on chemical functional groups

The paper reports, after a concise definition of the methodolo- gical bases of the approach, a view of the most recent advances in the analysis of mutual interactions among chemical groups in a molecule and of the interactions of chemical groups with fields of external origin. Attention is paid to the operational definition of through-space and through-bond substitution effects, to the mutual interaction effects on molecular conformations (for example, the anomeric effect), to the use of classical indexes for measuring propensity to geometry changes. Similar analyses are performed for molecules in solution, with the addition of one example in which a simple solute is perturbed by a complex biological system (DNA + counterions in solution). The effect of electronic excita- tion is also considered, in isolated molecules as well as in solution. Finer analyses on the effect of constant external fields on the geometry of molecular complexes are also briefly described.

The effect of intramolecular H-bonds on the aqueous solution continuum description of the N-protonated form of dopamine

Abstract The conformational properties in vacuo and in solution of N-protonated dopamine have been studied making use of ab initio SCF calculations in vacuo and free energy calculations in aqueous solution, in the framework of the polarizable continuum model (PCM), on the STO-3G, 4-31G and 6-31G∗ optimized geometries obtained in vacuo. The in vacuo energy profiles along a few sections of the potential energy surface turn out to be very close for the extended basis sets, while the STO-3G eresults are slightly dispalced. The largest difference between the minimal and the extended basis sets is found for the perpendicular arrangement, which is however the lowest energy profile with low barriers to the CCCN rotation both invacuo and in solution. The solvent stabilizes the trans over the gauche rotamers. Teh conformers without intramolecular H-bond between the −OH side chains are favored by the solvent, which makes the planari, anti conformers as stable as the corresponding conformers with an intramolecular H-bond in aqueous solution. The solvation free energy is considerably less basis set dependent than the potential energy in vacuo. The ab initio PCM results slightly favor the planar1 form over the planar2 form whereas the semiempirical AMSOL results of Urban, Cramer and Famini (J. Am. Chem. Soc. 114 (1992) 8226) do the opposite. The cavitation free energy is nearly independent of the basis set. The almost constant (about 4.4 kcal/mol) cavitation and dispersion-repulsion corrections do not affect the differential quantities.

Caco-2 cell permeability modelling: a neural network coupled genetic algorithm approach.

The ability to cross the intestinal cell membrane is a fundamental prerequisite of a drug compound. However, the experimental measurement of such an important property is a costly and highly time consuming step of the drug development process because it is necessary to synthesize the compound first. Therefore, in silico modelling of intestinal absorption, which can be carried out at very early stages of drug design, is an appealing alternative procedure which is based mainly on multivariate statistical analysis such as partial least squares (PLS) and neural networks (NN). Our implementation of neural network models for the prediction of intestinal absorption is based on the correlation of Caco-2 cell apparent permeability (Papp) values, as a measure of intestinal absorption, to the structures of two different data sets of drug candidates. Several molecular descriptors of the compounds were calculated and the optimal subsets were selected using a genetic algorithm; therefore, the method was indicated as Genetic Algorithm–Neural Network (GA-NN). A methodology combining a genetic algorithm search with neural network analysis applied to the modelling of Caco-2 Papp has never been presented before, although the two procedures have been already employed separately. Moreover, we provide new Caco-2 cell permeability measurements for more than two hundred compounds. Interestingly, the selected descriptors show to possess physico-chemical connotations which are in excellent accordance with the well known relevant molecular properties involved in the cellular membrane permeation phenomenon: hydrophilicity, hydrogen bonding propensity, hydrophobicity and molecular size. The predictive ability of the models, although rather good for a preliminary study, is somewhat affected by the poor precision of the experimental Caco-2 measurements. Finally, the generalization ability of one model was checked on an external test set not derived from the data sets used to build the models. The result obtained is of interesting practical application and underlines that the successful model construction is strictly dependent on the structural space representation of the data set used for model development.

Antioxidant Properties of Pterocarpans through Their Copper(II) Coordination Ability. A DFT Study in Vacuo and in Aqueous Solution

The antioxidant activity of 3,9-dimethoxy-4-prenylpterocarpan (bitucarpin A) and 3,9-dihydroxy-4,8-diprenylpterocarpan (erybraedin C) is supposed to be related to their copper coordination ability. Therefore several complexes with Cu(2+) of low-energy conformers of these two prenylated pterocarpans, whose conformational landscape was the subject of a prior B3LYP/6-31G* study (Alagona, Ghio, Monti Phys. Chem. Chem. Phys. 2004, 6, 2849), have been taken into account at the same computational level, with the metal ion described by effective core potentials in the LanL2DZ valence basis set. Their metal ion affinity (MIA) values have been determined and compared with the results obtained earlier with the same methods for the preferred binding sites of plicatin B, a prenylchalcone that can exist in E and Z configurations as well as in tautomeric forms. The stability order of the metalated species at the various coordination sites strongly depends on their position and nature. The spin density of the cation upon ligand coordination becomes vanishingly small, whereas the ligand spin density approaches 1. Thus the ligand is oxidized to a radical cation (Ligand(*+)), while Cu(II) is reduced to Cu(I). A very favorable MIA is obtained in vacuo when Cu(2+) is chelated between the prenyl and O lone pair moieties for both pterocarpans (MIA = 370 and 380 kcal/mol for bitucarpin A and erybraedin C, respectively). High affinity values are found also when the cation is sequestered within the two end groups (prenyl pi density and D ring) in the O(t) configuration (MIA = 371 and 373 kcal/mol for bitucarpin A and erybraedin C, respectively). In aqueous solution, the solvent effect dampens the free energy differences and reduces the MIA especially when the ion is remarkably exposed to the solvent. Conversely, when Cu(2+) is sequestered, the MIA decrease in solution is limited (MIA = 327 and 360 kcal/mol for bitucarpin A and erybraedin C, respectively). The solvent effect is significantly larger in plicatin B, where the MIA is lowered by 80 to 140 kcal/mol, probably because (a) the screening ability of the substituted phenolic ring is lower and (b) the positive charge on the ligand is less efficiently delocalized than in the four fused ring system of pterocarpans.