Improved Parametrization of Ion-DNA Interactions for MD Simulations of Dense DNA Systems

Abstract

Nucleic acids - highly charged polyanions - are often densely packed in biological systems. Counterions play an essential role in the biological processes involving densely packed DNA, such as chromosome remodeling and RNA folding. However, experimental measurements of the ion atmosphere around the nucleic acids remain elusive. All-atom molecular dynamics (MD) simulations can be used to characterize the ion atmosphere in great details; however, the usefulness of such simulations depends on the accuracy of the underlying computational model. Here, we test the accuracy of the current all-atom force field by carrying out an MD simulation of 64 parallel DNA duplexes (DNA array). Undesirably, we find both DNA array pressure and DNA distributions derived from these simulations to be inconsistent with the X-ray diffraction and osmotic pressure measurements. We find that the origin of such discrepancy is inaccurate description of ion interaction with the DNA phosphate. To improve the model, we fine-tune the ion-phosphate interaction parameters to reproduce experimental osmotic pressure of binary electrolyte solutions such as Na-dimethylphosphate. Using our improved model, we characterize ionic atmosphere in the DNA array. We find Mg to exhibit much stronger affinity to the DNA than Na: the concentration of Mg and Na ions inside the DNA array are ∼500 and ∼700 mM, respectively, although the ion concentration outside the DNA arrays is [Mg] = 20 and [Na] = 200 mM. Residence time analysis of Na/Mg in contact with DNA phosphate supports our assertion that Mg-phosphate interaction is much stronger than Na-phosphate one. We expect our successful re-parameterization of ion-phosphate interactions to find applications in MD simulations of other nucleic acid systems, in which ion-DNA interactions are critical, such as folding of RNA, ribozyme dynamics and the molecular mechanism of translation.