| Abstract |
RNAs ability to function as a biological catalyst (i.e. a ribozyme)
is showing great promise for biomedical technology and drug research
to create gene expression inhibitors that target viral and genetic
diseases. Due to ribozymes high negative charge and conformational
flexibility, metal ions play a key role in stabilizing active RNA
conformations and sometimes a catalytic role in the reaction
mechanism itself. The focus of this work is on developing a better
understanding of the conformational and divalent metal ion
requirements that are necessary in RNA catalysis. Early stages of the project involved a
systematic Density Functional Theory (DFT) study of Mg(II) ion binding
to phosphates and phosphoranes and other biological ligands. These
results were used in the development of and extension of the CHARMM27 force
field parameters specific to the study of reactive intermediates and divalent
metal ion binding in RNA enzymes. With this new force field, several
molecular dynamics simulations were carried out on the hammerhead
ribozyme system to understand more about the conformational changes, metal ion roles and
thio effects of importance to RNA catalysis. Finally, a discussion of
metal binding to DNA and its importance to stabilizing
phosphate-phosphate repulsions is given.
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