Abstract
The addition of small amounts of multivalent cations to solutions containing double-stranded DNA leads to inter-DNA attraction and eventual condensation. Surprisingly, the condensation is suppressed in double-stranded RNA, which carries the same negative charge as DNA, but assumes a different double helical form. Here, we combine experiment and atomistic simulations to propose a mechanism that explains the variations in condensation of short (25 base-pairs) nucleic acid (NA) duplexes, from B-like form of homopolymeric DNA, to mixed sequence DNA, to DNA:RNA hybrid, to A-like RNA. Circular dichroism measurements suggest that duplex helical geometry is not the fundamental property that ultimately determines the observed differences in condensation. Instead, these differences are governed by the spatial variation of cobalt hexammine (CoHex) binding to NA. There are two major NA-CoHex binding modes—internal and external—distinguished by the proximity of bound CoHex to the helical axis. We find a significant difference, up to 5-fold, in the fraction of ions bound to the external surfaces of the different NA constructs studied. NA condensation propensity is determined by the fraction of CoHex ions in the external binding mode.
Highlights
Charged DNA molecules are expected to repel each other, yet can be condensed by certain multivalent ions into structured aggregates [1,2,3]
The propensity for condensation, which is accompanied by precipitation of nucleic acids (NA) duplexes, was probed by measuring the fraction of duplexes remaining in solution after the addition of cobalt(III) hexammine (CoHex)
We examined 25 base-pair mixedsequence duplexes of RNA and DNA, a mixed sequence DNA:RNA hybrid, as well as a DNA homopolymer made of poly(dA):poly(dT)
Summary
Charged DNA molecules are expected to repel each other, yet can be condensed by certain multivalent ions into structured aggregates [1,2,3]. In vitro experiments on DNA in aqueous solution revealed that the cation-induced condensation requires the ion valence to be +3 or higher [1,8]. Trivalent cations, such as cobalt(III) hexammine (CoHex) or spermidine, can effectively condense DNA while divalent inorganic cations (e.g. Mg2+) alone cannot, suggesting the significant contribution of electrostatic interactions to the counterintuitive effective attraction between nucleic acids (NA). The general picture as well as the atomistic mechanism of NA condensation, including the role of hydration forces [12,29] or multivalent counterion correlations [14,26], are still incomplete and cannot be fully explained
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