| Description |
Advances in molecular dynamics (MD) simulation methodologies have enabled researchers to explore the conformational spaces of biological macromolecules more efficiently and quickly. Specifically, the development of enhanced sampling techniques has provided researchers with well-converged conformational ensembles of small macromolecules. It has been shown that converged simulations of small ribonucleic acids (RNA) such as tetranucleotides result in the population of experimentally unknown conformations, indicating RNA force field artifacts. However, although being imperfect, the current RNA force fields have also been useful in characterizing the varied interactions of ions and ligands with RNA. In this thesis, we analyze conformational ensembles of dinucleotide monophosphates generated with different force fields and water models with the aim of pinpointing force field problems. We also utilize the current force fields to demonstrate the preferential potassium binding to a buried ion-binding site in a ribosomal RNA molecule known as GTPase Associating Center (GAC) and also to elucidate an ion-dependent step in its unfolding pathway. We further show magnesium-independency of binding of a crystallographic 2-benzimidazole ligand to the Internal Ribosome Entry Site (IRES) of Hepatitis C virus (HCV), using MD simulations and docking. Our strategy is to assess simulation results with existing experimental data, and then also use simulation results to increase insight into RNA interactions and folding. These methods allow us to identify deficiencies of some current RNA force fields. |
