Unraveling Mg²⁺–RNA binding with atomistic molecular dynamics

Abstract

Interaction with divalent cations is of paramount importance for RNA structural stability and function. We report here a detailed molecular dynamics study of all the possible binding sites for Mg on an RNA duplex, including both direct (inner sphere) and indirect (outer sphere) binding. In order to tackle sampling issues, we develop a modified version of bias-exchange metadynamics, which allows us to simultaneously compute affinities with previously unreported statistical accuracy. Results correctly reproduce trends observed in crystallographic databases. Based on this, we simulate a carefully chosen set of models that allows us to quantify the effects of competition with monovalent cations, RNA flexibility, and RNA hybridization. Our simulations reproduce the decrease and increase of Mg affinity due to ion competition and hybridization, respectively, and predict that RNA flexibility has a site-dependent effect. This suggests a nontrivial interplay between RNA conformational entropy and divalent cation binding.

The mechanism of RNA base fraying: Molecular dynamics simulations analyzed with core-set Markov state models

“…SI 2B). Similar structures were also observed in previous works 22,81 and might be a consequence of both the short length of the duplex simulated here and the presence of restraints on the base-pair distances in the duplex.…”

Quantitative studies of an RNA duplex electrostatics by ion counting

“…E.g., monovalent cation occupancy in the dsDNA and dsRNA ion atmosphere is insensitive to the cation size across the alkali metal ions Na + , K + , Rb + , and Cs + , contrary to all-atom computational models and highlighting the need to reevaluate molecular mechanical force fields for solute-solvent and solventsolvent interactions. Our new experimental results for dsRNA-ion interactions provide the opportunity to test newly developed all-atom models of RNA-Mg 2+ interactions (70,72,74,76,77) and initiate a feedback loop between computation and experiment.…”

“…Experimental methods like ion counting can quantify the overall content of the ion atmosphere and energetics of competitive association of cations but does not provide information about the distribution of ions within the atmosphere. Computational models can in principle provide a thorough and deep understanding of ion-nucleic acid interactions, solvent-nucleic acid interactions, and the dynamic and energetic consequences of these interactions(31,35,60,(68)(69)(70)(71)(72)(73)(74)(75). However, the accuracy of such models cannot be assumed, and even matching to one a few prior experimental measurements in insufficient to establish the veracity of models for systems as complex and multi-variant as nucleic acid/ion interactions in solution.…”

Analyzing and Biasing Simulations with PLUMED

“…A more complicated example which has been taken from Ref. [21] and which also requires the WHOLEMOLECULES command to be used is shown in figure 10. In this case the reconstruction has been done using the following input file MOLINFO STRUCTURE=ref.pdb rna: GROUP ATOMS=1-258 mg: GROUP ATOMS=6580 wat: GROUP ATOMS=259-6579 # Make the RNA duplex whole.…”