Spectroscopic characterization of Mn2+ and Cd2+ coordination to phosphorothioates in the conserved A9 metal site of the hammerhead ribozyme

Hunsicker-Wang, L.M.; Vogt, Matthew; Hoogstraten, Charles G.; Cosper, Nathaniel J.; Davenport, Audrey M.; Hendon, Christopher H.; Scott, Robert A.; Britt, R. David; DeRose, Victoria J.

doi:10.1016/j.jinorgbio.2022.111754

Cited by 3 publications

(2 citation statements)

References 67 publications

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“…Finally, we investigate the effect of a phosphorothioate substitution at the phosphate···π position. Phosphorothioated nucleic acids are frequently used in therapeutics and nanotechnologies and were uncovered in the DNA and RNA of prokaryotes and eukaryotes. ,− At least two studies , reported enhanced stabilization of r(GNRA) tetraloops through melting and calorimetry experiments after the thio substitution of the (nt3)OP2 atom (nt3 = third nucleotide of the U-turn motif) that is involved in the phosphate···π contact (Figure ). The experimentally determined difference in Δ G is −2.9 kcal·mol –1 (37 °C) in ref and −4.7 kcal·mol –1 (25 °C) in ref .…”

Section: Introductionmentioning

confidence: 99%

Multiscale Modeling of Phosphate···π Contacts in RNA U-Turns Exposes Differences between Quantum-Chemical and AMBER Force Field Descriptions

Mráziková

Kruse

Mlýnský

et al. 2022

J. Chem. Inf. Model.

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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 using state-of-the-art quantum-chemical methods (QM) to characterize their physicochemical properties and to serve as a reference to evaluate AMBER force field (AFF) performance. We found that phosphate•••π interaction energies calculated with the 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 the QM and AFF result from a combination of missing polarization in the 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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Section: Introductionmentioning

confidence: 99%

Multiscale Modeling of Phosphate···π Contacts in RNA U-Turns Exposes Differences between Quantum-Chemical and AMBER Force Field Descriptions

Mráziková

Kruse

Mlýnský

et al. 2022

J. Chem. Inf. Model.

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“…Phosphorothioated nucleic acids are frequently used in therapeutics and nanotechnologies and were uncovered in DNA and RNA of prokaryotes and eukaryotes. 9,[37][38][39][40][41][42] At least two studies 9,43 reported enhanced stabilization of r(GNRA) tetraloops through melting and calorimetry experiments after thio-substitution of the (nt3)OP2 (nt3 = third nucleotide of the U-turn motif) atom that is involved in the phosphate…π contact (Figure 1). The experimentally determined difference in ∆G is −2.9 kcal.mol −1 (37°C) in ref.…”

Section: Introductionmentioning

confidence: 99%

Multiscale modelling of phosphate…π contacts in RNA U-turns reveals AMBER force-field deficiencies

Mráziková

Kruse

Mlýnský

et al. 2022

Preprint

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Phosphate…π, also called anion…π, contacts occur between nucleobases and phosphate OP oxygens in r(GNRA) and r(UNNN) U-turn motifs (N = A,G,C,U; R = A,G). We investigated these contacts in detail by using state-of-the-art quantum chemical methods (QM) to characterize some of their physico-chemical properties and to evaluate the ability of the AMBER force field (AFF) to describe these contacts. We found that AFF interaction energies of phosphate…π contacts calculated for model dimethyl phosphate…nucleobase systems are less stabilizing in comparison with double-hybrid DFT methods and that the minimum contact distances are stretched for all nucleobase systems. This distance stretch is also observed in large-scale AFF computations on several r(gcGNRAgc) tetraloop hairpins when compared to QM/MM. Further, classical molecular dynamics (MD) simulations of these tetraloop hairpins confirm this distance stretch and reveal shifted OP2/nucleobase positions when compared to experimental data extracted from high-resolution X ray/cryo EM structures (≤ 2.5 Å) of r(GNRA) tetraloops using the WebFR3D bioinformatic tool. We propose that discrepancies between QM and AFF are caused by a combination of missing polarization, too large AFF Lennard-Jones (LJ) radii of nucleobase carbon atoms and exaggerated short-range repulsion due to an approximate r−12 LJ repulsive term. We put these results in regard with those obtained in earlier investigations on lone pair…π contacts occurring in CpG Z-steps. Charge-transfer calculations do not support any significant n->π* donation effects and hence this label is inappropriate. We also investigated thiophosphate…π contacts for which we calculated less stabilizing interaction energies than for the phosphate…π contacts. We thus challenge suggestions that the experimentally observed enhanced thermodynamic stability of phosphorothioated r(GNRA) tetraloops can be straightforwardly explained by larger London dispersion.

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A review on recent advances in methods for site-directed spin labeling of long RNAs

Huang

2023

International Journal of Biological Macromolecules

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Spectroscopic characterization of Mn2+ and Cd2+ coordination to phosphorothioates in the conserved A9 metal site of the hammerhead ribozyme

Cited by 3 publications

References 67 publications

Multiscale Modeling of Phosphate···π Contacts in RNA U-Turns Exposes Differences between Quantum-Chemical and AMBER Force Field Descriptions

Multiscale Modeling of Phosphate···π Contacts in RNA U-Turns Exposes Differences between Quantum-Chemical and AMBER Force Field Descriptions

Multiscale modelling of phosphate…π contacts in RNA U-turns reveals AMBER force-field deficiencies

A review on recent advances in methods for site-directed spin labeling of long RNAs

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