ct6b00905_si_001.pdf (17.69 MB)
Development of Site-Specific Mg2+–RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations
journal contribution
posted on 2016-12-08, 00:00 authored by Lorenzo Casalino, Giulia Palermo, Nodira Abdurakhmonova, Ursula Rothlisberger, Alessandra MagistratoThe
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 ∼2.5 μs
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.