(214d) DNA At the Nanoscale: Interactions With Proteins, Polycations, and Surfaces

Developing a fundamental understanding of the interactions of DNA with surfaces and with other biomolecules is important for numerous emerging biomedical and biomaterials technologies. In this poster we present three systems where we use molecular simulations to study the thermodynamics and molecular-level structural details of these interactions. In the first study, we examine how DNA is affected by two platinum-based anticancer drugs that, by design, covalently bind to and damage DNA to slow the growth of tumor cells. Recognition of this drug-DNA damage by repair proteins leads to drug-resistant tumors. We find that differences in the drug-DNA structure, and in the free energy of deforming the drug-DNA molecule during protein binding, explain differences in protein recognition of the anticancer drugs [1,2]. In the second study, we examine the behavior of single-stranded DNA (ssDNA) near model hydrophobic and hydrophilic surfaces, which is important for technologies based on DNA self-assembly. We find that ssDNA adsorbs strongly to both surfaces, although different types of interactions between the ssDNA, the surface, and water molecules govern adsorption [3]. In the third study, we examine the interactions between DNA and a novel class of polycations, which are effective biomaterials for gene delivery. We reveal molecular-level interactions in polycation-DNA binding using simulations with multiple levels of detail, thus complementing experimental data with otherwise inaccessible details such as binding free energy, local charge neutralization, and the structure of polycation-DNA complexes [4-6]. Most importantly, we have found that a close coupling of simulations and experiments enriches and accelerates biomedical and biomaterials research.

[1] Elder, R. M.; Jayaraman, A., Role of structure and dynamics of DNA with cisplatin and oxaliplatin adducts in various sequence contexts on binding of HMGB1a. Mol. Sim. 2012, 38, (10), 793-808.

[2] Elder, R. M.; Jayaraman, A., Sequence-Specific Recognition of Cancer Drug-DNA Adducts by HMGB1a Repair Protein. Biophys. J. 2012, 102, (10), 2331-2338.

[3] Elder, R. M.; Jayaraman, A., Structure and Thermodynamics of ssDNA Oligomers near Hydrophobic and Hydrophilic Surfaces: A Molecular Simulation Study. (submitted).

[4] Elder, R. M.; Emrick, T.; Jayaraman, A., Understanding the Effect of Polylysine Architecture on DNA Binding Using Molecular Dynamics Simulations. Biomacromolecules 2011, 12, (11), 3870-3879.

[5] Elder, R. M.; Jayaraman, A., Coarse-grained simulation studies of effects of polycation architecture on structure of the polycation and polycation-polyanion complexes. Macromolecules 2012, 45, (19), 8083-8096.

[6] Elder, R. M.; Jayaraman, A., DNA Binding Affinity of Nuclear Localization Sequence-based Polycations. (in preparation).