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Understanding ion-mediated compaction of nucleic acids

Ions play essential roles in governing the structure and function of nucleic acids, due to the large negative charge associated with the nucleic acid backbone. The addition of even small amounts of multivalent, positively charged (or counter-) ions induces inter- helix attraction in DNA and thus efficiently packages the extended polymer(s) into compact toroids. In vivo, the ion-mediated interactions are critical to proper compaction and function of DNA in the chromatin. Similar physical processes are responsible for packaging DNA into viral capsids. Mean-field theories do not account for the correlations that appear to be important for ion-mediated NA-NA attraction, and the standard “electrostatics only” PB approach misses many other physically relevant effects. Models that go beyond mean-field have been developed and provided general insights into the physics of the ion-mediated DNA attraction. However, to make progress, these approaches rely on drastic approximations to NA shape (perfect cylinder, sphere) and/or simplified interaction potentials (e.g. scaled Coulomb). As a result, they cannot provide the detailed picture we seek. Fully explicit solvent simulations could, in principle, provide the right level of detail, but they often face prohibitive sampling issues in these strongly correlated, highly charged systems. These limitations become especially severe in the case of biologically important, but more structurally complex, charged polyamines such as spermine and spermidine essential for cell function. The absence of efficient computational models that adequately describe the multivalent ion – NA system hinders progress in areas fundamental to biomedical science (outlined above) that need detailed understanding of the process of DNA or RNA compaction and interaction induced by multivalent ions and charged polyamines. We combine the efforts of three research groups to pioneer a new and tightly integrated approach that will bridge various levels of theory and experiment with the goal of understanding ion-induced nucleic acid interactions.