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Multiscale Modelling of Phosphate…π Contacts in RNA U-turns Exposes Differences Between Quantum-ChemicalM and AMBER Force Field Descriptions

Abstract : Phosphate…π, also called anion…π, contacts occur between nucleobases and anionic phosphate oxygens (OP2) in r(GNRA) and r(UNNN) U-turn motifs (N = A,G,C,U; R = A,G). These contacts were investigated by using state-of-the-art quantum-chemical methods (QM) to characterize their physico-chemical properties and to serve as reference to evaluate AMBER force field (AFF) performance. We found that phosphate…π interaction energies calculated with AFF for dimethyl phosphate…nucleobase model systems are less stabilizing in comparison with double-hybrid DFT and that minimum contact distances are larger for all nucleobases. These distance stretches are also observed in large-scale AFF vs. QM/MM computations and classical molecular dynamics (MD) simulations on several r(gcGNRAgc) tetraloop hairpins when compared to experimental data extracted from X ray/cryo EM structures (res. ≤ 2.5 Å) using the WebFR3D bioinformatic tool. MD simulations further revealed shifted OP2/nucleobase positions. We propose that discrepancies between QM and AFF result from a combination of missing polarization in AFF combined with too large AFF Lennard-Jones (LJ) radii of nucleobase carbon atoms in addition to an exaggerated short-range repulsion of the r−12 LJ repulsive term. We compared these results with earlier data gathered on lone-pair…π contacts in CpG Z-steps occurring in r(UNCG) tetraloops. In both instances, charge-transfer calculations do not support any significant n->π* donation effects. We also investigated thiophosphate…π contacts that showed reduced stabilizing interaction energies when compared to phosphate…π contacts. Thus, we challenge suggestions that the experimentally observed enhanced thermodynamic stability of phosphorothioated r(GNRA) tetraloops can be explained by larger London dispersion.
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Submitted on : Thursday, November 17, 2022 - 9:23:35 PM
Last modification on : Friday, November 25, 2022 - 10:04:43 AM


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Klaudia Mráziková, Holger Kruse, Vojtěch Mlýnský, Pascal Auffinger, Jirí Sponer. Multiscale Modelling of Phosphate…π Contacts in RNA U-turns Exposes Differences Between Quantum-ChemicalM and AMBER Force Field Descriptions. Journal of Chemical Information and Modeling, In press. ⟨hal-03857441⟩



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