Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department


Major Professor

H. Lee Woodcock, Ph.D.

Committee Member

Brian Space, Ph.D.

Committee Member

Arjan Van der Vaart, Ph.D.

Committee Member

Sameer Varma, Ph.D.


Chemistry, Molecular Physics, Physical Chemistry, Thermodynamic Free Energy


The computation of free energy is pivotal to understanding the fundamental nature of chemical phenomena. That is, whether a specific molecular outcome occurs spontaneously or is inherently unfavorable. The need to do this with consistent accuracy begs for the use of quantum mechanical (QM) methods. However, techniques for directly computing free energy differences with QM or mixed QM/MM methods are untenable, as the computational expense is quite exorbitant. At present, the most feasible approach for obtaining QM/MM free energies is employing the so-called indirect cycle, which relies on accurately computing free energy differences between low (e.g., molecular mechanical, MM) and high (e.g., QM/MM) levels of theory.

Unfortunately, the most prevalent equilibrium methods prove insufficient due to the poor configurational overlap between MM and QM/MM. Herein, methods are introduced, both in the equilibrium (Chapter 2 & 3) and non-equilibrium (Chapter 4) regime that improve the calculation of free energies between levels of theory. This is followed by an evaluation of the validity for a common approximation invoked (Chapter 5}) that short cuts much of the challenges in computing free energies between levels of theory, and concludes with a study on how employing ``better'' MM levels of theory (Chapter 6) can facilitate indirect QM/MM free energy calculations.