Solvation, structure and dynamics of nucleic acids: Insights from simulations

The research presented in this dissertation focuses on the development and application of theoretical models to nucleic acid systems. Chapter 1 describes the development of an approach to calculate the free energy differences between different nucleic acid sequences, with or without a ligand present. The utility of this technique is demonstrated by the calculation of the solvation free energies of the five nucleic acid bases adenine, guanine, cytosine, thymine and uracil. The material presented in Chapters 2, 3 and 4 involves the application of molecular dynamics (MD) simulations to a small RNA tetraloop structure. Chapter 2 is a comparative study that demonstrates the importance of accurately treating the electrostatic interactions in such highly charged systems as nucleic acids and in the protein ubiquitin. Appendix B contains further discussion of the specific effects observed in the MD simulations of the tetraloop. Chapter 3 probes the amount of sampling obtainable in MD simulations of RNA structures. It also discusses a method for increasing this sampling given the inherent rigidity of RNA. Chapter 4 is a study which shows that MD simulations can be used to study structural rearrangements in nonhelical nucleic acid structures. The results presented in this chapter show that an A-form to B-form transition can be observed in the stem portion of the DNA analog of the RNA tetraloop using unrestrained MD simulations. Appendices A and C contain supplementary material to Chapters 1 and 3 which was not suitable for publication.