Solvent effects in quantum chemical-based methods : I. defined-sector explicit solvent in the continuum model approach for computational prediction of PKa and II. algorithmic strategies towards inclusion of first solvation shell effects

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Chemical, biochemical and catalytic processes occur in environments where the specifics of structure, molecular reactivity and chemical properties are often very different than in an isolated gas phase environment. It is therefore important to have good predictive models that include the solution environment. Continuum models can in principle handle the majority of the bulk effects that depend on ion screening (dielectric constant). In contrast, the “non-electrostatic” or short-range interactions, such as hydrogen bonding or charge transfer, are not accounted for in the continuum model, and various strategies to include these effects are available. One such strategy is the continuum-cluster methodology, which is an implicit-explicit approach, whereby a small number of explicit solvent molecules are included to capture the short-range interactions and the resultant cluster is treated with a continuum model to capture the long-range or bulk energetics. This thesis work focuses on elucidating a strategy to systematize the number and placement of the explicit solvent molecules included in the cluster for modeling solution phase properties, in particular, dissociation constants. A new model, the Defined-Sector Explicit Solvent in Continuum Cluster Model (DSES-CC), provides a systematic basis for the inclusion of explicit solvation within the continuum model ansatz, resulting in a transferable explicit solvent arrangement for all systems containing a carboxylic or carboxylate moiety. The DSES-CC model achieves benchmark accuracy for prediction of first and second dissociation constants (pKa1 and pKa2 values) of carboxylic acids. Explicit solvation is shown to be essential for accurate prediction of dissociation constants particularly due to the sensitivity of the property to small changes in free energy of dissociation. All calculations carried out in the development and implementation of DSES-CC have been done with COSab, the locally modified version of the COSMO in GAMESS software package.