Advances in computing capabilities have facilitated the application of quantum mechanical methods to increasingly larger and more complex chemical systems, including weakly interacting and biologically relevant species. One such ab initio-based composite methodology, the correlation consistent composite approach (ccCA), has been shown to be reliable for the prediction of enthalpies of formation and reaction energies of main group species in the gas phase to within 1 kcal mol-1, on average, of well-established experiment, without dependence on experimental parameterization or empirical corrections. In this collection of work, ccCA has been utilized to determine the proton affinities of deoxyribonucleosides within an ONIOM framework (ONIOM-ccCA) and to predict accurate enthalpies of formation for organophosphorus compounds. Despite the complexity of these systems, ccCA is shown to result in enthalpies of formation to within ~2 kcal mol-1 of experiment and predict reliable reaction energies for systems with little to no experimental data. New applications for the ccCA method have also been introduced, expanding the utility of ccCA to solvated systems and complexes with significant noncovalent interactions. By incorporating the SMD solvation model into the ccCA formulation, the Solv-ccCA method is able to predict the pKa values of nitrogen systems to within 0.7 pKa unit (less than 1.0 kcal mol-1), overall. A hydrogen bonding constant has also been developed for use with weakly interacting dimers and small cluster compounds, resulting in ccCA interaction energies for water clusters and dimers of the S66 set to within 1.0 kcal mol-1 of well-established theoretical values.