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An osmometric method and a water-accessible surface area (ASA) analysis are developed to quantify and interpret the interactions of the remarkable osmolyte glycine betaine (GB) with molecular surfaces in water. GB, lacking hydrogen bond donors which is unable to compete with water to interact with anionic and amide oxygen demonstrated its effectiveness as an osmolyte in the Escherichia coli cytoplasm.

Potential of mean force (PMF) calculations and a calibrated quantum mechanical and molecular mechanical (QM/MM) potential are used for studying the proton transfer energetics in carbonic anhydrase II (CAII) associated with different orientations of the acceptor group. The results of the perturbation analysis and the [PHI] analysis have tested the mechanistic proposals in which the stepwise proton hole transfer pathway is proposed.

A proton transfer through water is achieved by generating a hydroxide by first protonating the acceptor and then transferring the hydroxide toward the donor through water that is described as the transfer of a 'proton hole' from the acceptor to the donor. The study establishes that the 'proton hole' transfer is important for proton transport in many complex molecular systems.

Effective quantum mechanical/molecular mechanical (QM/MM) methods were studied in order to understand vectorial proton transport in biomolecular ion pumps. It was found that quantitative energetics and new mechanistic insights can be obtained for complex processes that involve the ionization and transfer of protons in water and the enzyme carbonic anhydrase and the fluctuations of water molecules peripheral to the water wire were found to make larger impact on the proton transfer energetics.

The overall goal of the study is to rigorously test typical quantum mechanical and molecular mechanics (QM/MM) protocols in order to provide a clear picture of the accuracy and relative importance of various factors in determining the accuracy. The results will provide useful guidance to the quantitative application of QM/MM simulations in general.

The importance of treating van der Waals interactions between the quantum mechanical (QM) and molecular mechanical (MM) atoms in hybrid QM/MM simulations is investigated. The study indicates that the efforts in improving the reliability of QM/MM methods for energetical properties in the condensed phase should focus on components other than van der Waals interactions between QM and MM atoms.

The quasi-chemical theory and electronic structure outcome on inner-sphere H(H2O)(sub n)(super +) group are used to discuss the absolute hydration free energy of H(super +)(aq). It is observed that this volume is not thermodynamically measurable which results in improper alignment of tables of absolute hydration free energies of ions in water.