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

Area of Science:

• Structural Biology
• Computational Chemistry
• Biophysics

Background:

• Phosphate···π (anion···π) contacts are crucial interactions between phosphate oxygens and nucleobases in RNA structures like U-turn motifs.
• Accurate modeling of these interactions is essential for understanding RNA stability and function.
• Existing molecular mechanics force fields, such as the AMBER force field (AFF), require rigorous evaluation against high-level quantum chemical (QM) methods.

Purpose of the Study:

• To characterize the physicochemical properties of phosphate···π contacts using QM methods.
• To evaluate the performance of the AMBER force field (AFF) in modeling these interactions.
• To identify the sources of discrepancies between QM calculations and AFF simulations.

Main Methods:

• High-level quantum-chemical (QM) calculations (double-hybrid DFT) on model systems.
• AMBER force field (AFF) calculations for interaction energies and distances.
• QM/MM computations and classical molecular dynamics (MD) simulations on RNA tetraloop hairpins.
• Comparison with experimental data from X-ray/cryo-EM structures using WebFR3D.

Main Results:

• AFF underestimates the stabilizing interaction energies of phosphate···π contacts compared to QM.
• AFF predicts larger minimum contact distances between phosphate oxygens and nucleobases than QM.
• MD simulations confirm these distance stretches and show shifted positions, consistent with experimental data.
• Discrepancies are attributed to missing polarization and inaccurate Lennard-Jones parameters in the AFF.

Conclusions:

• The AMBER force field has limitations in accurately representing phosphate···π interactions due to missing polarization and inappropriate Lennard-Jones parameters.
• These findings challenge the explanation of enhanced thermodynamic stability in phosphorothioated RNA via increased London dispersion.
• Accurate modeling of non-covalent interactions in nucleic acids requires force fields that properly account for electronic polarization effects.