Structural Stability of Nucleic Acids and Peptides

Abstract

In chapter one, two simple models are used to estimate the electrostatic contributions to the stiffness of short DNA fragments. The first model views DNA as two strands that are appropriately parameterized and are wrapped helically around a straight cylinder radius equal to the radius of the DNA molecule. The potential energy of the DNA due to phosphate-phosphate electrostatic interactions is evaluated assuming that the charges interact through Debye-Hückle potentials. This potential energy is compared with the potential energy as computed using our second model in which DNA is viewed as two helical strands wrapping around a curved tube whose cross-section is a disk of radius equal to the radius of the DNA. The results are compared with counterion condensation models and experimental data (Guo et al. J. Phys. Chem. B, 2008, 112, 16163-16169). In chapter two, the fidelity of translation selection begins with the base pairing of codon-anticodon complex between the mRNA and tRNAs. Binding of cognate and near-cognate tRNAs induces 30S subunit of the ribosome to wrap around the ternary complex, EF-Tu(GTP)aa-tRNA. We have proposed that large thermal fluctuations play a crucial role in the selection process. The binding energies of over a dozen unique site-bound magnesium structural motifs are investigated and provide insights into the nature of interaction of divalent metal ions with the ribosome (Guo et al. Proc. Nat. Acad. Sci. 2011, 108, 3947-3951). In chapter three, we use extensive molecular dynamics simulations to study a series of stapled alpha helical peptides over a range of temperatures in solution. The peptides are found to exhibit substantial variations in predicted helicities that are in good agreement with the experimental value. In addition, we find significant variation in local structural flexibility of the peptides with the position of the linker, which appears to be more closely related to the observed differences in activity than the absolute alpha helical stability (Guo et al. Chem. Biol. Drug. Des. 2010, 75, 348-359.). In chapter four, the alpha helical conformation and structural stability of single and double stapled all-hydrocarbon cross-linked p53 peptides in solution and when bound to MDM2 is investigated. We determined the effects of the peptide sequence, the stereochemistry of the cross-linker, the conformation of the double bond in the alkene bridge, the length of the bridge, on the relative stability of the alpha helix structure. The conformation population distribution indicates a fully helical state and several partially folded states. The distribution of dihedral pairs of the stapled peptides in the bound state indicates a significant population around the alpha helical region. Sequences over which the linker spans tend to have the highest helical occupancy. Significant helical content is observed for a double stapled p53 peptide at 575 K. The probability to form native contacts is increased when the stapled peptides are bound to MDM2. The distribution of the end-to-end distance of the peptides is bimodal.