(3ac) Modeling Complex Structures in Nucleic Acids

Since the discovery of DNA, researchers have been attempting to decode the detailed structure, properties, and abilities of this molecule.  At first approximation, DNA can be thought of as a ling, regular, double-stranded helix encoding the genomic information of life.  However, on closer analysis DNA has been found to take on a wide variety of complex shapes and function both in vitro and in vivo.  DNA can be single-, double-, triple-, and even quadruple-stranded in nature and can bind in both the Watson-Crick conformations and also in a wealth of non-canonical configurations that add to its inherent flexibility, structure, and activity.  Elucidating the varied structures and behaviors of DNA has historically been an experimental endeavor, due in large part to the difficulties in capturing nucleic acid’s complex motions and functions in a tractable computation model.  However, as the applications of DNA expand and computational power increases, simulation models are playing an increasingly important role in DNA understanding and engineering.  

Throughout the course of my doctoral work, I developed new nucleic acid models able to successfully capture the complex structures and behaviors of DNA and RNA that previously have been left out of such coarse grained models.  I also designed specific experimental tests able to validate nucleic acid simulation models.  My new models are able to reproduce simple systems such as experimentally gathered single-stranded DNA melting curves and B-form double-stranded DNA.  In addition, much more complex systems such as double-stranded DNA twisting behavior (P- and S-DNA transitions), triple-stranded conformations found in H-DNA and during strand invasion, and quadruple-stranded structures such as G-quartets, can be modeled.  These complex structures are vital components of cellular recognition, transcription, and regulatory pathways, DNA repair, and telomeres and may play a role in understanding wider, multi-faceted issues in cancer, aging, and disease.  Although many of these complex structures have yet to be characterized and there is only indirect experiment evidence for their functions, molecules relying on non-canonical interactions have begun to be used in nanotechnology, genetic engineering, and therapeutic applications.  I anticipate that more in depth understanding  of nucleic acids will provide a platform upon which I can harness DNA’s power and ability in order to engineer these molecules for novel applications.