We present the development of a force field for simulation of nucleic acids and proteins. Our approach began by obtaining equilibrium bond lengths and angles from microwave, neutron diffraction, and prior molecular mechanical calculations, torsional constants from microwave, NMR, and molecular mechanical studies, nonbonded parameters from crystal packing calculations, and atomic charges from the fit of a partial charge model to electrostatic potentials calculated by ab initio quantum mechanical theory. The parameters were then refined with molecular mechanical studies on the structures and energies of model compounds. For nucleic acids, we focused on methyl ethyl ether, tetrahydrofuran, deoxyadenosine, dimethyl phosphate, 9-methylguanine-1 -methylcytosine hydrogen-bonded complex, 9-methyladenine-1 -methylthymine hydrogen-bonded complex, and 1,3-dimethyluracil base-stacked dimer. Bond, angle, torsional, nonbonded, and hydrogen-bond parameters were varied to optimize the agreement between calculated and experimental values for sugar pucker energies and structures, vibrational frequencies of dimethyl phosphate and tetrahydrofuran, and energies for base pairing and base stacking. For proteins, we focused on , ' maps of glycyl and alanyl dipeptides, hydrogen-bonding interactions involving the various protein polar groups, and energy refinement calculations on insulin. Unlike the models for hydrogen bonding involving nitrogen and oxygen electron donors, an adequate description of sulfur hydrogen bonding required explicit inclusion of lone pairs.

A trans (T) and two gauche (G1 and G2) conformers have been identified for protonated dopamine in the gas phase upon ab initio calculations up to the QCISD(T)/6-31G*//HF/6-31G* and MP2/6-311++G**// MP2/6-311++G** levels and based on B3LYP/6-31G* optimizations in DFT. Free energy differences at 298 K and 1 atm were calculated to be 3.2-5.6 kcal/mol between T and G1, and about 0 kcal/mol between the G2 and G1 conformers. The OH groups are nearly coplanar with the benzene ring and form an O-H‚‚‚O-H intramolecular hydrogen bond in their most stable arrangement. Using the free energy perturbation method through Monte Carlo simulations, relative solvation free energies were evaluated in aqueous solution at T ) 310 K and 1 atm. Ab initio/Monte Carlo torsional potential curves were calculated along pathways where small rotations about the C(ring)-C β and C β -C R axes were allowed. No stable rotamers but the gas-phase optimized structures were identified. The T -G1 and G2 -G1 relative solvation free energies were calculated at -2.63 ( 0.31 and 1.34 ( 0.43 kcal/mol, respectively. The calculated T -G1 total free energy difference is at least 0.6 ( 0.3 kcal/mol in aqueous solution, predicting a G:T ratio of at least 75:25 as compared to the experimental value of 58:42. The calculated result is sensitive both to the applied basis set and to the level of the electron correlation considered upon obtaining the internal energy. When dopamine acts in a biological environment, its protonated form is presumably surrounded by counterions, mainly by chloride anions. If a chloride counterion, set at a N‚‚‚Cl separation of 6 Å to estimate the upper bound of the counterion effect on a solvent separated DopH + ion, is also considered in the solution simulations, the T -G1 relative solvation free energy takes a value of -0.55 ( 0.95 kcal/mol. Computer modeling shows that a close chloride ion largely modifies the solution structure in the immediate vicinity of protonated dopamine. The effect is different for the gauche and the trans conformers and leads to a decrease of the solvation preference for the trans form. Although the DopH + ‚‚‚Clion pair separated by a single water molecule is not favored in the bulk aqueous solution, such arrangement is possible in more restricted regions, e.g., in a receptor cavity or when passing lipid membranes. At such places one could expect an increase in the G conformer over the T form at pH ) 7.4 and T ) 310 K as compared to the G:T ratio found in D 2 O solution of dopamine at pH ) 7.

The gauche-trans equilibrium of 1,2-ethanediol was investigated in the gas phase and in aqueous solution with ab initio quantum chemical calculations and Monte Carlo simulations. MP2/6-31G*//6-31G* energy calculations and HF/6-31G* normal frequency analyses were carried out for the tGg', gGg', g'Gg' (gauche), and tTt (trans) isomers. The free energy of the most stable tGg' isomer with an intramolecular hydrogen bond is more negative by 2.8 kcal/mol than the trans form at T = 298 K. This coincides with the experimental finding of no trans rotamer in the gas phase. The effect of hydration on the equilibrium ratio was followed by statistical perturbation calculations using the Monte Carlo method at T = 298 K and P = 1 atm. In solution only three conformers were considered. On the basis of the gas-phase rigid-rotation potential map, two different paths were considered for the tTt to tGg' transformation and a single path for the tGg' to gGg' change. The solvation free energy for the trans rotamer is more negative by 1.2 kcal/mol than that for tGg'. Also gGg' is stabilized by about 1.0 kcal/mol upon solvation. Considering both total internal and hydration free energies, the solution contains about 97% gauche conformers. This is basically in accordance with recent NMR results. The solution structure was analyzed with use of energy pair and radial distribution functions obtained after taking 6000K configurations. Positions of the water molecules around the solutes were determined by statistical averaging of about 4500 snapshots of the solution configurations. The first hydration shell of the 1,2-ethanediol solute contains approximately six water molecules. There are, on average, four water molecules strongly hydrogen bonded to the solute in the tTt conformation. This number decreases for gauche conformers with intramolecular hydrogen bonds in solution. The water-solute hydrogen bonds are slightly bent with a favorable O-H distance of 1.8-1.9 Á. Water molecule acceptors in these bonds are more localized than those acting as proton donors.

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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.

DFT geometry optimizations have been performed at the B3LYP/6-31G* level in the gas phase and at the IEF-PCM/B3LYP/6-31G* level in tetrahydrofuran (THF) and aqueous solutions using scaled radii for the diketo and ketoenol forms of acetylacetone and cyclohexanedione. To evaluate basis set effects, starting from the aforementioned minima, the 6-311ϩϩG** optimized structures have been obtained. A number of complexes of both systems including one explicit water molecule have been considered up to the B3LYP/6-311ϩϩG** level, for cyclohexanedione taking into account the B3LYP/6-31G* basis set superposition errors as well. The diketo-ketoenol interconversion mechanisms have been investigated at the B3LYP/6-31G* level in vacuo. Interestingly, the geometric constraint due to the presence of the ring facilitates the description of the reaction mechanism in cyclohexanedione. Despite the very different flexibility of the two systems that in the case of acetylacetone prevents a straightforward interconversion of the diketo to the most stable of its ketoenol forms, both reactions occur with a very high barrier (about 62-63 kcal/mol), unaffected by continuum solvents, that decreases by 2.5-3.5 kcal/mol after the inclusion of thermal corrections. The barriers are almost halved, becoming ϳ31-35 kcal/ mol, for the addition of a single water molecule according to various model reaction paths. Thermal corrections are limited (0.8 -1.6 kcal/mol) for those adducts. The formation of a 1,1-diol, explored in the case of acetylacetone, might facilitate the obtainment of the most stable diketo conformation, featuring the carbonyl groups in distinct orientations. Inclusion of dispersion and basis set effects via the G2MP2 protocol does not alter the relative stability of both system tautomers. In contrast, the G2MP2 interconversion barriers for the isolated systems in vacuo are close to the B3LYP ones, whereas they turn out to be somewhat higher than the free energy-based B3LYP barriers in the presence of a catalytic water molecule.

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