This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.We request computational resources for the free energy calculations of two distinct systems, the relaxation of DNA supercoils by topoisomerase and the interaction of DNA with Polyamidoamine (PAMAM) dendrimers. Both systems involve understanding the driving forces behind the ability of nanometer sized objects (i.e. an enzyme and a dendrimer respectively) to affect the mechano-chemistry of long stretches of DNA. Topoisomerases are enzymes of quintessential importance to cellular processes and are an important chemotherapeutic target. We are calculating the free energy profiles of relaxation of DNA supercoils by Human Topoisomerase I with and without the potent anti-cancer drug Topotecan. PAMAM dendrimers show promise as a potential system for delivery of genes to cells for therapeutic purposes. We plan to study the interactions between a generation 3 PAMAM dendrimer and a 24 base-pair dsDNA using molecular dynamics simulations. Rather than start with the dendrimer complexed with the DNA, umbrella sampling will be used to pull a dendrimer toward the strand of DNA in order to see how the interaction is initiated. The reaction coordinate for these simulations will be the distance between the centers of mass of the two molecules. Previous simulations on the interactions between dendrimers and negatively charged surfaces show that the morphology of the dendrimer changes as the nanoparticle approaches the surface. We expect, therefore, that the final dendrimer-DNA complex will involve structural changes in both the dendrimer and the DNA. The weighted histogram analysis method will be used to unbias the distribution function of the reaction coordinate and generate a free energy prole. Asphericity of the dendrimer will be calculated to analyze the morphology of the dendrimer as it approaches the DNA.
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