All-Atom MD Simulation of DNA Condensation Using Ab Initio Derived Force Field Parameters of Cobalt(III)-Hexammine

Abstract

It is well established that the presence of the trivalent cobalt(III)-hexammine cation (CoHex) at submillimolar concentrations leads to bundling (condensation) of double-stranded DNA molecules, which is caused by DNA-DNA attraction induced by the multivalent counterions. However, the detailed mechanism of this process is still not fully understood. Furthermore, in all-atom molecular dynamics (MD) simulations, spontaneous aggregation of several DNA oligonucleotides in the presence of CoHex has previously not been demonstrated. In order to obtain a rigorous description of CoHex-nucleic acid interactions and CoHex-induced DNA condensation to be used in MD simulations, we have derived optimized force field parameters of the CoHex ion. They were obtained from Car-Parrinello molecular dynamics simulation of a single CoHex ion in the presence of 125 water molecules. The new set of force field parameters reproduces the experimentally known transition of DNA from B- to A-form, and qualitatively describes changes of DNA and RNA persistence lengths. We then carried out a 2 μs long atomistic simulation of four DNA oligomers each consisting of 36 base pairs in the presence of CoHex. We demonstrate that, in this system, DNA molecules display attractive interactions and aggregate into bundle-like structures. This behavior depends critically on the details of the CoHex interaction with DNA. A control simulation with a similar setup but in the presence of Mg does not induce DNA-DNA attraction, which is also in agreement with experiment.

A multiscale analysis of DNA phase separation: from atomistic to mesoscale level

“…Similarly to the result of our previous work (51), the system shows DNA–DNA attraction and aggregation of DNA into fibre-like bundles induced by CoHex 3+ (Figure 2). DNA fibres are formed across the periodic boundaries in all three independent simulations (see Supplementary Figure S2A–C).…”

“…In the present work, we used all-atom MD simulations based on the CHARMM27 force field. However, we recently demonstrated similar behaviour in all-atom simulations that showed DNA-DNA attraction and bundling using both CHARMM36 and AMBER parameters (51). It should furthermore be of interest to investigate how the mesoscale simulation results depend on the CG topology comparing different CG DNA models, which include DNA sequence specificity (37,47).…”

“…The CHARMM27 force field is used in all simulations, supplemented with Car-Parrinello MD (CPMD) optimised CoHex 3+ parameters obtained in our previous work (51).…”

A Bottom-Up Coarse-Grained Model for Nucleosome–Nucleosome Interactions with Explicit Ions

“…Hence, the mean volume average Mg 2+ ion concentration in the simulation cell (50 mM) corresponds to a significantly lower experimental bulk concentration. 47 The optimized hydrated Mg(H 2 O) 6 2+ model 48 and optimized CoHex 3+ model 40 were used for multivalent ions. About 50 mM K + and 35 mM Na + ions were added to provide a background salt environment close to physiological conditions.…”

Observation of reversal in twist-stretch coupling of RNA suggests a unified mechanism for the opposite couplings of DNA and RNA

“…For simulations, the initial structures of B-DNA and A-RNA were built using the nucleic acid builder of AMBER [19,23,24,27,28]. The force fields of CoHex 3+ , Mg 2+ and Na + cations were described by the recently proposed ion models [19,[29][30][31]. The bulk cation concentrations were confirmed before the production runs of 1000 or 600 ns [32], and all microscopic structural parameters for DNA and RNA duplexes were calculated using the program Curves+ [33].…”