Modeling studies electrostatic solvation free energies

It is clear in both of these studies that the small cavity size (which fails to entirely contain all of the atoms given standard van der Waals radii) causes electrostatic solvation free energies to be seriously overestimated — the difference in the 4-nitroimidazole system seems much too large to be physically reasonable. This overestimation would be still more severe were a correct DO model to have been used (i.e., one which accounted self-consistently for the full solute polarization using eq 30). Nevertheless, the D02 results may be considered qualitatively useful, to the extent that they identify trends in tautomer electrostatic solvation free energies. 

Influence of the molecular environment on the structure and dynamics of molecular subsystems will be outlined referring to the solvation free energy (Chapter 4). Implicit solvent models based on the Poisson-Boltzmann (PB) equation and the Generalized Born (GB) model is discussed in 5 and 6. The PB or GB models are used for studies of molecular electrostatic properties and allow proper assignments of positions of protons (hydrogen atoms) within the given (bio)molecular structure. 

A theoretical study based on MP2/6-31+G(d,p) and HF/6-31G(d) ab initio quantum mechanical calculations coupled with Langevin dipoles (LD) and polarised continuum (PCM) solvation models have been carried out by Florian and Warshel [387] to achieve a first systematic study of the free energy surfaces for the hydrolysis of methylphosphate in aqueous solution. The important biological implication of this work is the fact that since the energetics of both the associative and the dissociative mechanics are not too different, the active sites of enzymes can select either mechanism depending on the particular electrostatic environment. This conclusion basically means that both mechanisms should be considered, and this fact seems to contradict some previous studies which have focused on phosphoryl transfer reactions. 

For many chemical problems, it is crucial to consider solvent effects. This was demonstrated in our recent studies on the hydration free energy of U02 and the model reduction of uranyl by water [232,233]. The ParaGauss code [21,22] allows to carry out DKH DF calculations combined with a treatment of solvent effects via the self-consistent polarizable continuum method (PCM) COSMO [227]. If one aims at a realistic description of solvated species, it is not sufficient to represent an aqueous environment simply as a dielectric continuum because of the covalent nature of the bonding between an actinide and aqua ligands [232]. Ideally, one uses a combination model, in which one or more solvation shells (typically the first shell) are treated quantum-mechanically, while long-range electrostatic and other solvent effects are accounted for with a continuum model. Both contributions to the solvation free energy of U02 were... 

The present chapter thus provides an overview of the current status of continuum models of solvation. We review available continuum models and computational techniques implementing such models for both electrostatic and non-electrostatic components of the free energy of solvation. We then consider a number of case studies, with particular focus on the prediction of heterocyclic tautomeric equilibria. In the discussion of the latter we center attention on the subtleties of actual chemical systems and some of the dangers of applying continuum models uncritically. We hope the reader will emerge with a balanced appreciation of the power and limitations of these methods. 

An example employing a more realistic force field can also be found in the application of sensitivity analysis to study the determinants of the structural and thermodynamical properties of the protein avian pancreatic polypeptide (APP). It was found that the size and shape of the protein was determined to a large extent by electrostatic interactions, whereas the free energy of the protein was more sensitive to the surface-area-dependent solvation energy terms that modeled hydrophobic effects. Consequently, it is possible to develop an ad hoc force field that is designed to describe certain classes of (bio)molecular properties properly. The failure of such an ad hoc force field to describe properties of other types does not necessarily indicate that this force field is useless, rather, caution should be exercised in any attempt to apply it to other properties. 

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