Approximate quantum mechanical calculations, particularly density functional theory, have been successfully
used in the previous few decades to help understand the activity of metalloproteins towards various
fundamental reactions important both to humans and other forms of life. Examples include Cytochrome P450
which helps metabolize waste products in the body, nitrogenase which takes part in the nitrogen cycle
important for food growth, and hemoglobin and myoglobin which regulate oxygen and nitric oxide transport in
the body. However, these theoretical methods often have serious difficulty in the treatment of transition metal
containing compounds even smaller than these metalloproteins, making interpretation of mechanism in these
systems uncertain. This difficulty, in turn makes it difficult to redesign these proteins, create artificial versions,
and to design drug targets for them. Phaseless auxiliary-field quantum Monte Carlo (ph-AFQMC) on graphical
processing units and correlated sampling offers an accurate and scalable alternative to traditional methods.
This application involves the development of a localized orbital formulation of this technique to push it from one
only used on small systems to one used reliably on large systems. Then this method will be used both as a
benchmark for more approximate methods and used as a correction to cluster models of these metalloproteins.
Using this method, questions regarding the mechanism of oxidation in Cytochrome P450, N-N bond cleavage
in nitrogenase, and autoxidation in hemoglobin as well as questions regarding the binding of small molecules
such as O2, CO, and NO to the heme of hemoglobin and myoglobin will be answered. The work will be
undertaken at Columbia University under the mentorship of Prof. Richard Friesner in the chemistry department,
an expert in metalloprotein modeling, in collaboration with Prof. David Reichman at Columbia, an expert in
Quantum Monte Carlo. The supercomputing facilities at Columbia and at remote facilities such as Oak Ridge
National Lab Leading Computing Facility and NSF XSEDE include ample CPU and GPU resources. The
fellowship training plan involves publishing in high impact journals and presenting at conferences for both the
theoretical chemistry community and the biochemistry community. It also includes the opportunity to mentor
graduate students. The career development plans includes attending workshops organized by the Office of
Postdoctoral Affairs as well continuing in a leadership role in the Columbia University Postdoctoral Society.