Graduation Year
2023
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Chemistry
Major Professor
Henry L. Woodcock, Ph.D.
Committee Member
Wayne Guida, Ph.D.
Committee Member
James Leahy, Ph.D.
Committee Member
Robert Deschenes, Ph.D.
Keywords
Computational Chemistry, Molecular Dynamics Simulations, (S)QM/MM, Free Energy Simulations, Molecular Docking
Abstract
Molecular dynamics (MD) is a powerful technique that can be used to provide informationabout a system over time. MD simulations can be used to explore behaviors of many systems such as protein-ligand interactions protein-protein interactions. Additionally, these simulations can be used to generate trajectories of a system to further be used for free energy simulations. The work discussed in Chapter 2 involves the use MD simulations to identify potential drug candidates capable of binding to and stabilizing the nuclear binding domain of the Cystic Fibrosis Transmembrane Conductance Regulator protein. Using ProBiS, we were able to find a potential binding site as well as potential small molecules to bind to said site. The stabilizing effects of these drugs were then tested experimentally using ΔF508- NBD1 expressed in E. coli. DSF experiments were conducted, ultimately revealing that two of the tested small molecules binds to our protein, but showing destabilizing effects rather than the stabilizing effects we’d hoped to see. In Chapter 3, MD simulations were used to assess the stability of a protein-protein complex, 14-3-3 and Raf. Through Molecular Dynamics simulations we found that dephosphorylation of Ser259 affected the stability of the complex, while Raf orientation had minor effects on the complex stability. Lastly, we used MD simulations in Chapter 4, as a starting point to improve free energy simulations by adopting the optimized protocols discovered by our collaborator[1] and employing the use of force matching to improve conformational overlap between the “low level” and “high level” systems. Here, we finally achieved better convergence and configurational overlap betwixt our forcematched parameter sets and those from our higher level of theory (3OB).
Scholar Commons Citation
Rodman, Taylor A., "Employing the Use of Molecular Dynamics to Explore Protein Stability and Optimize Free Energy Protocols" (2023). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10739
