Modeling Free Energies of Solvation and Transfer

Abstract

The free energy of transfer of a solute from one medium to another, which is the free energy of solvation if the first medium is the gas phase and the second is a liquid-phase solution, controls all solvation and partitioning phenomena. The SM5.4 quantum mechanical solvation model allows for the calculation of (i) partitioning free energies between the gas phase and a solvent (i.e., free energies of solvation) or (ii) partitioning free energies between two solvents. The model provides a framework for interpreting the factors responsible for differential solvation effects and can be used to predict solvation effects on chemical equilibria and kinetics-examples in this chapter include partitioning of the nucleic acid bases between water and chloroform, solvation effects on anomeric conformational equilibria, and solvation effects on the rate of the Claisen rearrangement.A collection of solute molecules will partition between two (or more) phases so as to equalize the concentration-dependent chemical potential of the solute in all phases (1). This behavior has far reaching consequences in chemistry. For instance, a molecule might have very high specific activity against a target enzyme, but if its concentration in aqueous biophases or fatty tissues is extremely low it may be inefficacious as an oral drug (since it must be carried by the bloodstream and, if the enzyme is locatedintracellularly, it must pass through a lipid bilayer membrane). A second example of medium effects on equilibria is that the fraction of molecules in any one of several potentially accessible conformations can depend significantly on solvent, and this structural equilibrium may have significant effects on molecular properties, recognition, and reactivity. As a final example, medium effects on reaction rates can be viewed as changes in the relative equilibrium concentrations of reactants and activated complexes on going from one environment to the next. These examples 'Corresponding authors

Implicit Solvation Models: Equilibria, Structure, Spectra, and Dynamics

“…A topic of particular interest for molecular design is the extent to which solvation or transfer free energies can be decomposed into contributions from different portions of a molecule (e.g., atoms, functional groups, etc.). Because they compute free energies of solvation using atomic charges and surface tensions, GB−ST models have lent themselves, in particular, to this sort of analysis. ,,,,,,− The transferability of chloroform/water partition coefficients for functional groups in a series of substituted purine and pyrimidine bases was evaluated using this approach (the transferability was predicted to be quite good) . Luque et al have recently described a formalism for decomposing PCM-ST solvation free energies in an analogous fashion …”

“…These are typically added to the cavitation free energy as calculated by the method of Pierotti, , or Claverie's , generalization of Pierotti's equation, to compute the full first-solvation-shell contribution. The alternative approach of using the SASA and parametrized atomic surface tensions, as practiced by the Minnesota and Barcelona groups for the SM x ,,− ,− and MST-ST ,− models, respectively, does not attempt to quantitate the relative contributions of these different first-solvation-shell interactions; it aims rather to account for their sum and also, by virtue of being semiempirically fitted, to correct for any systematic inaccuracies in the electrostatic treatment. In the case of the SM x models, organic solvents are treated generally, with surface tensions for a given level of theory being a function of certain macroscopic solvent parameters, like surface tension, index of refraction, a free-energy-based solvent-acidity parameter, etc.…”

“…The dielectric descreening algorithm of Still et al is based on integrating the solvent free energy density over the volume occupied by the solvent, an old idea , cleverly and powerfully adapted to a new context. The most widely used solvation models adopting this procedure are the original generalized Born/surface area (GBSA) approach of Still and co-workers, ,, including the subsequent extensions and adaptations of several groups, ,− in which the generalized Born electrostatics are combined with a classical MM treatment of the solute, and the SM x models of Cramer, Truhlar, and co-workers, ,,,− ,− ,− ,− ,− , in which generalized Born electrostatics are employed in a quantum mechanical treatment of the solute. In both of these approaches, semiempirical atomic surface tensions are used to account for nonelectrostatic solvation effects.…”

“…An important development in the past few years has been the parametrization of atomic surface tensions not only in terms of properties of the atoms of the solute but also in terms of solvent properties. ,,− By using widely available solvent descriptors, this has allowed the development of several SM x solvation models that are applicable not only to water but to any organic solvent. These models are specifically SM5.4, ,,,,, SM5.2R, ,, SM5.0R, − and SM5.42R. − …”

“…Prediction of the partitioning behavior of a solute between two liquid phases has motivated extensive parametrization efforts for different solvent models. The most complete such parametrizations are the SM5 suite of universal solvation models which have been parametrized on over 2000 pieces of free energy data in 91 solvents. − Additional work has been motivated primarily by the relationship between bioavailability of drugs and their partitioning behavior between aqueous and nonpolar phases, where the latter may be either a model solvent or an actual biomembrane. ,,,, …”