Benchmarking the Drude Polarizable Force Field Using the r(GACC) Tetranucleotide

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• Polarizable force fields, like the Drude FF, aim to improve biomolecular simulations by including atomic polarizability.
• Previous studies showed success with duplex nucleic acids and proteins.
• However, their performance with flexible, single-stranded RNA remains unverified.

Purpose of the Study:

• To benchmark the Drude polarizable force field's ability to model flexible, single-stranded RNA structures.
• To assess the force field's accuracy in capturing the conformational dynamics of short RNA sequences.

Main Methods:

• Multimicrosecond molecular dynamics simulations of the r(GACC) tetranucleotide.
• Utilizing the Drude polarizable force field.
• Analysis of structural distributions and comparison with experimental NMR data.

Main Results:

• The Drude FF failed to match the experimental structural distribution for r(GACC), regardless of initial conformation.
• The expected major NMR conformation was not observed.
• Simulations resulted in stable, anomalous structures favoring base-pairing and electrostatics over base stacking, persisting over microsecond timescales.

Conclusions:

• The Drude FF currently exhibits a misbalance of forces, hindering accurate modeling of single-stranded RNA.
• The force field may not be suitable for simulating flexible or noncanonical RNA structures without further refinement.