UC Irvine

The further study of the fundamental physical properties of nucleic acids, can have far reaching impacts. These highly dynamic biological macromolecules can be difficult to study as their behavior can be dictated by processes that act on timescales that range over several orders of magnitude. Certain experiments of nucleic acids in solution can scratch the surface of the sub millisecond regime, but experiments that probe processes much faster than that can become difficult, and often do not contain significant atomistic detail, with the notable exception of site-specific liquid-state NMR. From the nanosecond to microsecond, biological macromolecules can be readily studied by simulation. Through the use of molecular dynamics I've studied an exciting feature of nucleic acids, the Hoogsteen base pair. In recent years support for its biological relevance has increased. Understanding the mechanics of how this base pair forms and it's energetic comparison to the Watson-Crick base pair, can lead to developing a greater understanding of it's role in biology. Often comparing to experiments I have seen a stark contrast in the abilities of DNA and RNA to maintain this base pair. In an attempt to explain this difference, I have seen how cooperative shifts in the sugar puckers of DNA, that are necessary for the Hoogsteen base pair to form, are unobtainable in more rigid RNA sugars. I have also been able to observe how the dynamic equilibrium that exists between Watson-Crick and Hoogsteen base pairs within DNA can be influenced by the binding of intercalating drugs, such as echinomycin. Finally, I have combined previous computational techniques to develop a novel way of obtaining time correlation functions from accelerated milestoning techniques, with potential application to biological systems such as the Watson-Crick Hoogsteen base pair transition.