Ionization pK,s for a large set of molecules were calculated using reactivity models developed in the computer program SPARC. SPARC uses relatively simple computational algorithms based on fundamental chemical structure theory to estimate ionization pK,s of organic molecules strictly from molecular structure. Molecular structures are broken at each essential single bond into functional units with intrinsic properties. Reaction centers (acid or base) are identified and the impact of appended molecular structure on ionization p& is quantified by perturbation theory. Resonance, electrostatic, solvation and H-bonding models have been developed and tested on 4338pK,s for 3685 compounds. The RMS deviation for the acids and the amino reaction center was 0.36 pK, units whereas that for the in-ring N and = N reaction centers was 0.41. Microscopic ionization constants, zwitterionic constants, isoelectric points, and molecular speciation as a function of pH can be calculated using the SPARC models. solubility, partitioning phenomena, and chemical reactivity are all highly dependent upon the state of ionization in the solution phase. The ionization pK, of an organic compound is vital to environmental exposure assessment because it can be used to define the degree of ionization and the propensity for sorption to soil and sediment by cation exchange. This, in turn, can determine mobility, reaction kinetics, bioavailability, complexation, etc. In addition to being highly significant in evaluating environmental fate and effects, acid-base ionization equilibria provide an excellent arena for testing the electrostatic effects models in the computer program SPARC. Because the gain or loss of protons results in a change in molecular charge, these processes are extremely sensitive to electric field effects within the molecule. The object of this study was to test these reactivity models utilizing the large pK, databases that are available. These databases are relatively reliable (f a few tenths of a pK, unit) for smaller more soluble molecules.Numerous investigators have attempted to predict ionization pK,s using various approaches such as ab initio [I, 21 and semiempirical [3,4] methods. The energy differences between the protonated state and the unprotonated state are small compared to the total binding energy of the reactant involved. This presents a problem for ab initio computational methods that calculate absolute energy values. Computing the relatively small energy differences needed for the analysis of chemical reactivity from absolute energies requires extremely accurate calculations. Hence, the aforementioned calculations were limited to a small subclass of molecules. A more aggressive attempt has been made by Klopman et. al., [5,6]. They estimated the p&s for some 2400 molecules (? = 0.846) based on QSAR using the Multi-CASE program. Despite the relatively large number of pK,s calculated their calculator was limited to the estimation of the first pK, [6]. Recently, we described our approach to predict numerous physical pr...

The prototype computer program SPARC has been under development for several years to estimate physical properties and chemical reactivity parameters of organic compounds strictly from molecular structure. SPARC solutesolute physical process models have been developed and tested for vapor pressure (at any temperature), heat of vaporization (at 25C and the boiling point), diffusion coefficient (at 25C) and boiling point (at any pressure) for a relatively large number of organic molecules. The RMS deviation error of the predicted the vapor pressures, heats of vaporization (at any temperature) and boiling points (at any pressure) were close to the intralaboratory experimental errors.

Solvation models, based on fundamental chemical structure theory, were developed in the SPARC mechanistic tool box to predict a large array of physical properties of organic compounds in water and in non-aqueous solvents strictly from molecular structure. The SPARC self-interaction solvation models that describe the intermolecular interaction between like molecules (solute-solute or solvent-solvent) were extended to quantify solute-solvent interaction energy in order to estimate the activity coefficient in almost any solvent. Solvation models that include dispersion, induction, dipole-dipole and hydrogen bonding interactions are used to describe the intermolecular interaction upon placing an organic solute molecule in any single or mixed solvent system. In addition to estimation of the activity coefficient for 2674 organic compounds, these solvation models were validated on solubility and liquid/liquid distribution coefficient in more than 163 solvents including water. The RMS deviations of the calculated versus observed activity coefficients, solubilities and liquid/liquid distribution coefficients were 0.272 log mole fraction, 0.487 log mole fraction and 0.44 log units, respectively.

Enolase, a glycolytic enzyme that catalyzes the dehydration of 2-phospho-d-glycerate (PGA) to form phosphoenolpyruvate (PEP), is a homodimer in all eukaryotes and many prokaryotes. Here, we report the crystal structure of a complex between yeast enolase and an equilibrium mixture of PGA and PEP. The structure has been refined using 29 854 reflections with an F/sigma(F) of >/=3 to an R of 0.137 with average deviations of bond lengths and bond angles from ideal values of 0.013 A and 3.1 degrees , respectively. In this structure, the dimer constitutes the crystallographic asymmetric unit. The two subunits are similar, and their superposition gives a rms distance between Calpha atoms of 0.91 A. The exceptions to this are the catalytic loop Val153-Phe169 where the atomic positions in the two subunits differ by up to 4 A and the loop Ser250-Gln277, which follows the catalytic loop Val153-Phe169. In the first subunit, the imidazole side chain of His159 is in contact with the phosphate group of the substrate/product molecule; in the other it is separated by water molecules. A series of hydrogen bonds leading to a neighboring enolase dimer can be identified as being responsible for ordering and stabilization of the conformationally different subunits in the crystal lattice. The electron density present in the active site suggests that in the active site with the direct ligand-His159 hydrogen bond PGA is predominantly bound while in the active site where water molecules separate His159 from the ligand the binding of PEP dominates. The structure indicates that the water molecule hydrating carbon-3 of PEP in the PEP --> PGA reaction is activated by the carboxylates of Glu168 and Glu211. The crystals are unique because they have resolved two intermediates on the opposite sides of the transition state.