Observed solvation free-energy

It is possible to go beyond the SASA/PB approximation and develop better approximations to current implicit solvent representations with sophisticated statistical mechanical models based on distribution functions or integral equations (see Section V.A). An alternative intermediate approach consists in including a small number of explicit solvent molecules near the solute while the influence of the remain bulk solvent molecules is taken into account implicitly (see Section V.B). On the other hand, in some cases it is necessary to use a treatment that is markedly simpler than SASA/PB to carry out extensive conformational searches. In such situations, it possible to use empirical models that describe the entire solvation free energy on the basis of the SASA (see Section V.C). An even simpler class of approximations consists in using infonnation-based potentials constructed to mimic and reproduce the statistical trends observed in macromolecular structures (see Section V.D). Although the microscopic basis of these approximations is not yet formally linked to a statistical mechanical formulation of implicit solvent, full SASA models and empirical information-based potentials may be very effective for particular problems. 

Solvent effects on chemical equilibria and reactions have been an important issue in physical organic chemistry. Several empirical relationships have been proposed to characterize systematically the various types of properties in protic and aprotic solvents. One of the simplest models is the continuum reaction field characterized by the dielectric constant, e, of the solvent, which is still widely used. Taft and coworkers [30] presented more sophisticated solvent parameters that can take solute-solvent hydrogen bonding and polarity into account. Although this parameter has been successfully applied to rationalize experimentally observed solvent effects, it seems still far from satisfactory to interpret solvent effects on the basis of microscopic infomation of the solute-solvent interaction and solvation free energy. 

A Gsol w designates the solvation free energy of the given ion in water. The corresponding observed information is compiled and analyzed in Ref. 4. 

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A radius to study tautomeric equilibria in the 2-, 4-, and 5-hydroxyoxazole systems (the keto tautomers are referred to as oxazolones). Tautomers illustrated above in parentheses were not considered and hydroxyl rotamers were not specified. In the first two systems, tautomers 22 and 25 are predicted by AMI to be about 14 kcal/mol more stable than the nearest other tautomer in their respective equilibria. Differences in tautomer solvation free energies do not overcome this gas-phase preference in either case, and the oxazolones are predicted to dominate the aqueous equilibrium, as is observed experimentally [266],... 

The Born model of solvation overestimates solvation free energies but indicates the general trends correctly. Potential inversion, as observed in many other systems containing two identical oxidizable or reducible groups separated by an unsaturated bridge (Scheme 1.4), can be rationalized in the same manner. 

It is important to re-emphasize that the electrostatic component of the solvation free energy is not a physical observable. Thus, it is impossible to assert on any basis other... 

Surprisingly, the low solubility of small-sized particles does not stem from a weak interaction of particles with their surrounding water environment (77). For example, the heat of solvation of methane in water at ambient temperature is of similar magnitude as the heat of vaporization of pure liquid methane (80). The positive solvation free energy of small apolar particles at low temperatures is the consequence of negative solvation entropy, which overcompensates for the negative solvation enthalpy. It is widely believed that this entropy penalty is caused by the orientation order introduced to the hydration-shell water molecules as they try to maintain an intact hydrogen bond network (77). Parallel to the entropy decrease observed for low... 

Furthermore, when the solvation free energy is included, the difference in conformational free energy between the native and modeled loops is reduced as shown in Figure 1 for CDRLl. Similar plots were obtained for CDRL2 and CDRL3 (data not shown). The gap in energy observed when only side chains were optimized is reduced but still present for CDRLl (Table Ilb). There is no modeled CDRLl loop that had a lower conformational gas phase free energy than the native CDR loop. 

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