Molecular dynamics of DNA and free energy studies of protein-DNA interactions

The biological functions of nucleic acids including information storage, replication and transcription are ultimately linked to the chemical elements of base pair sequence and the biophysical elements of energetics, structure and molecular motions. My thesis is focused on the understanding of the fine structural properties of DNA and the influence of environmental conditions of water activity and salt on the DNA structure and motions by use of molecular dynamics (MD) simulations. The thesis is organized into four main projects: (a) Molecular dynamics study of packing effects in an oligonucleotide crystal structure; (b) Simulations of B′ DNA and the sequence effects of A-tract DNA bending and bendability; (c) Effects of DNA structure to localized sodium ions; (d) Energy component analysis of protein-DNA binding. The first project, compares the MD results on a B DNA sequence in the crystal with those for the same sequence in solution and provides a basis for a purely theoretical study of crystal packing effects. The MD results for this case indicated the influence of crystal packing on the structure to be local and not global. In the second project, the results from MD simulation of nine unique sequences including five examples of A-tract DNA oligonucleotide dodecamer duplexes are used to examine salient issues in the structural chemistry of ApA steps and A-tract induced axis bending. The results from MD indicate that bending and flexibility of base-pair steps in DNA are highly correlated and the MD description of A-tract-induced axis bending shows most consistency with the non A-tract, general sequence model. The third project examines the effect of ions on the differential stability of a B-form helix using the MD results on a dodecamer and two longer oligonucleotides, which exhibit A-tract-induced axis bending. Plots of axis bending and proximity of ions to the bending locus were generated as a function of time and revealed a strong linear correlation, supporting the idea that mobile cations play a key role in local helix deformations of DNA and indicating ion proximity just precedes the bending event. The fourth project is a detailed theoretical analysis of the thermodynamics and functional energetics of protein-DNA binding in the EcoRI endonuclease-DNA complex. The standard free energy of complexation is considered in terms of a thermodynamic cycle of seven distinct steps decomposed into a total of 24 well-defined components. The results indicate that van der Waals interactions and water release favor complexation, while electrostatic interactions, considering both intramolecular and solvation effects, prove unfavorable. The results from this thesis contribute to our understanding of the dynamical structure of nucleic acids in solution, effects of sequence on DNA structure and axis bending important in molecular recognition process and contribute to an improved understanding of the thermodynamics of nucleic acid-protein binding process.