Kostenbader, Kenneth. Using functional links between distinct RNA enzymes to guide computational studies and uncover biocatalytic strategies. Retrieved from https://doi.org/doi:10.7282/t3-wd4w-7m24
DescriptionA useful way to build a predictive understanding of biocatalysis is to isolate the critically conservedfeatures of dissimilar enzymes that catalyze the same reaction, while at the same time identify subtle variations that provide insight to guide design. In the last seven years, the number of ribozyme classes that have been structurally characterized has more than doubled, and for the first time, there is compelling evidence of a common set of catalytic strategies. This dissertation outlines a general approach to the investigation of novel ribozymes by describing a series of molecular simulation results for the pistol ribozyme (Psr), contextualized by the existing mechanistic understandings of the Hammerhead ribozyme. Chapter 2 provides a detailed perspective of the computational tools that were used in this study, while Chapter 3 outlines new developments that could aid in the application of these tools to the studies described in Chapters 4 and 5. Chapter 4 presents an in-depth comparison of the pistol and hammerhead catalytic mechanisms as inferred from MD simulations, and Chapter 5 closes with insights into the rate-limiting step in pistol’s catalysic mechanism as inferred from QM/MM simulations.