Base sequence specificity of counterion binding to DNA: what can MD simulations tell us?

Abstract

Nucleic acids are highly charged biopolymers whose secondary structure is strongly dependent on electrostatic interactions. Solvent molecules and ions are also believed to play an important role in mediating and directing both sequence recognition and interactions with other molecules, such as proteins and a variety of ligands. Therefore, to fully understand the biological functions of DNA, it is necessary to understand the interactions with the surrounding counterions. It is well known that monovalent counterions can bind to the minor groove of DNA with consecutive sequences of four, or more, adenine and thymine (A-tracts) with relatively long residence times. However, much less is known about their binding to the backbone and to the major groove. In this work, we used molecular dynamics simulations to both investigate the interactions between the backbone and major groove of DNA and one of its physiological counterions (Na+) and evaluate the relationship between these interactions and the nucleotide sequence. Three dodecamers, namely CGAAAATTTTCG, CGCTCTAGAGCG, and CGCGAATTCGCG, were simulated using the Toukan–Rahman flexible SPC water model and Smith and Dang parameters for Na+, revealing a significant sequence dependence on the ion binding to both backbone and major groove. In the absence of experimental data on the atomistic details of the studied interactions, the reliability of the results was evaluated performing the simulations with additional sets of potential parameters for ions and solvent, namely the Ȧqvist or the Joung and Cheatham ion parameters and the TIP3P water model. This allowed us to evaluate the results by verifying which features are preserved independently from the parameters adopted.

Representation of DNA environment: Spiral staircase distribution function

“…The magnesium ions are rigidly condensed on phosphates and form solvent‐shared ion‐pairs, while Na + ions form a contact pairs with OP groups. This is qualitatively consistent with the results of Atzori …”

“…Two systems were simulated: (1) one DNA fragment in solution of 18,983 water molecules and 34 Na + (molar concentration of sodium is about 0.1 M), (2) one DNA fragment in solution of 19,000 water molecules and 17 Mg 2+ (molar concentration is about 0.05 M). Additional sodium chloride was not added to the system to form saline following the works …”

“…This DNA fragment contains random sequence of GC and AT base pairs. The DNA in solution of sodium or magnesium ions was chosen because such system has been sufficiently well studied and there is a lot of information on this subject …”

Structure-guided DNA–DNA attraction mediated by divalent cations

“…Simulations ( 9–10 , 20 ), previous experiments ( 5 , 22–23 ) and our study show no evidence of DNA condensation by monovalent cations alone. The reasons behind this observation are likely that the monovalent cations have weak major groove binding ( 35 ). In addition to their weak binding, their low valence can not afford to create a positive charge pattern on the DNA surface backbone.…”

“…Specific binding to minor groove can also create a charge pattern which in principle attracts favorably the backbone of the adjacent pair. Further studies are underway to explore the mechanism of DNA attraction in transition metal ions such as Mn 2+ ion which is known to bind preferentially to the minor grooves in A-tracks ( 35 ).…”