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  4. Development of Site-Specific Mg2+-RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations
 
research article

Development of Site-Specific Mg2+-RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations

Casalino, Lorenzo
•
Palermo, Giulia  
•
Abdurakhmonova, Nodira
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2017
Journal of Chemical Theory and Computation

The vital contribution of Mg2+ ions to RNA biology is challenging to dissect at the experimental level. This calls for the integrative support of atomistic simulations, which at the classical level are plagued by limited accuracy. Indeed, force fields intrinsically neglect nontrivial electronic effects that Mg2+ exerts on its surrounding ligands in varying RNA coordination environments. Here, we present a combined computational study based on classical molecular dynamics (MD) and Density Functional Theory (DFT) calculations, aimed at characterizing (i) the performance of five Mg2+ force field (FF) models in RNA systems and (ii) how charge transfer and polarization affect the binding of Mg2+ ions in different coordination motifs. As a result, a total of similar to 2.5 mu s MD simulations (100/200 ns for each run) for two prototypical Mg2+-dependent ribozymes showed remarkable differences in terms of populations of inner-sphere coordination site types. Most importantly, complementary DFT calculations unveiled that differences in charge transfer and polarization among recurrent Mg2+-RNA coordination motifs are surprisingly small. In particular, the charge of the Mg2+ ions substantially remains constant through different coordination sites, suggesting that the common philosophy of developing site-specific Mg2+ ion parameters is not in line with the physical origin of the Mg2+-RNA MD simulations inaccuracies. Overall, this study constitutes a guideline for an adept use of current Mg2+ models and provides novel insights for the rational development of next-generation Mg2+ FFs to be employed for atomistic simulations of RNA.

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