The value of the proton hydration free energy, ΔGhyd(H+), has been quoted in the literature to be from −252.6 to −262.5 kcal/mol. In this article, we present a theoretical model for calculating the hydration free energy of ions in aqueous solvent and use this model to calculate the proton hydration free energy, ΔGhyd(H+), in an effort to resolve the uncertainty concerning its exact value. In the model we define ΔGhyd(H+) as the free energy change associated with the following process: ΔG[H+(gas)+H2nOn(aq)→H+(H2nOn)(aq)], where the solvent is represented by a neutral n-water cluster embedded in a dielectric continuum and the solvated proton is represented by a protonated n-water cluster also in the continuum. All solvated species are treated as quantum mechanical solutes coupled to a dielectric continuum using a self consistent reaction field cycle. We investigated the behavior of ΔGhyd(H+) as the number of explicit waters of hydration is increased from n=1 to n=6. As n increases from 1 to 3, the hydration free energy decreases dramatically. However, for n=4–6 the hydration free energy maintains a relatively constant value of −262.23 kcal/mol. These results indicate that the first hydration shell of the proton is composed of at least four water molecules. The constant value of the hydration free energy for n⩾4 strongly suggests that the proton hydration free energy is at the far lower end of the range of values that have been proposed in the literature.

We calculate free energy changes of ionization reactions in aqueous solvent using a self-consistent reaction field method. In the calculations all species are treated as quantum mechanical solutes coupled to a solvent dielectric continuum. We show for a series of substituted imidazole compounds that both absolute and relative pK a values for the deprotonation of nitrogen on the imidazole ring can be obtained with an average absolute deviation of 0.8 units from experiment. This degree of accuracy is possible only if the solutes are treated at the correlated level using either G2 type or density functional theory. Inconsistencies in published experimental free energies of hydration that might undermine the reliability of the calculated absolute pK a values are discussed.

The mechanism of the hydrolysis reaction of guanosine triphosphate (GTP) by the protein complex Ras-GAP (p21(ras) - p120(GAP)) has been modeled by the quantum mechanical-molecular mechanical (QM/MM) and ab initio quantum calculations. Initial geometry configurations have been prompted by atomic coordinates of a structural analog (PDBID:1WQ1). It is shown that the minimum energy reaction path is consistent with an assumption of two-step chemical transformations. At the first stage, a unified motion of Arg789 of GAP, Gln61, Thr35 of Ras, and the lytic water molecule results in a substantial spatial separation of the gamma-phosphate group of GTP from the rest of the molecule (GDP). This phase of hydrolysis process proceeds through the low-barrier transition state TS1. At the second stage, Gln61 abstracts and releases protons within the subsystem including Gln61, the lytic water molecule and the gamma-phosphate group of GTP through the corresponding transition state TS2. Direct quantum calculations show that, in this particular environment, the reaction GTP + H(2)O --> GDP + H(2)PO(4) (-) can proceed with reasonable activation barriers of less than 15 kcal/mol at every stage. This conclusion leads to a better understanding of the anticatalytic effect of cancer-causing mutations of Ras, which has been debated in recent years.

The energy of dimerization of two N-methylacetamide (NMA) molecules in vacuum is calculated using density functional theory. Natural orbital analysis suggests that the dimerization energy of -6.6 kcal/mol is predominantly due to the (NsH‚‚‚OdC) donor-acceptor interaction. The gas phase to water hydration free energies and the free energies of transfer from the aqueous phase to liquid alkane of hydrogen bonded, (NsH‚‚‚OdC), and nonbonded, (NsH,OdC), groups are calculated using a continuum solvent model. On the basis of these calculations, we estimate the free energy of forming an amide hydrogen bond in the context of the NMA dimer in water and in liquid alkane as ∼-1 and ∼-5 kcal/mol, respectively. The relevance of these calculations to processes such as protein folding and membrane insertion of proteins is discussed.