Empirical corrections to the Amber RNA force field with Target Metadynamics

Abstract

The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics simulations. We here use experimental data collected from high-resolution X-ray structures to attempt an improvement of the latest version of the AMBER force field. A modified metadynamics algorithm is used to calculate correcting potentials designed to enforce experimental distributions of backbone torsion angles. Replica-exchange simulations of tetranucleotides including these correcting potentials show significantly better agreement with independent solution experiments for the oligonucleotides containing pyrimidine bases. Although the proposed corrections do not seem to be portable to generic RNA systems, the simulations revealed the importance of the alpha and beta backbone angles on the modulation of the RNA conformational ensemble. The correction protocol presented here suggests a systematic procedure for force-field refinement.

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• Unravelling Mg${}^{2+}$-RNA binding with atomistic molecular dynamics
• Exploring RNA structure and dynamics through enhanced sampling simulations
• Predicting the kinetics of RNA oligonucleotides using Markov state models
• Recent Advances in Maximum Entropy Biasing Techniques for Molecular Dynamics
• Refinement of molecular dynamics ensembles using experimental data and flexible forward models
• Boosting ensemble refinement with transferable force field corrections: synergistic optimization for molecular simulations
• MDRefine: a Python package for refining Molecular Dynamics trajectories with experimental data
• Automatic learning of hydrogen-bond fixes in an AMBER RNA force field