Assessment of RNA Force Fields for Dynamic Docking of Small Molecules Using Multicanonical MD Simulations

Area of Science:

• Computational Chemistry
• Structural Biology
• Drug Discovery

Background:

• Molecular dynamics (MD) simulations are crucial for studying RNA-ligand interactions in drug development.
• Assessing the accuracy of RNA force fields is limited by MD sampling efficiency and docking protocols.

Purpose of the Study:

• To evaluate the performance of modern AMBER-based RNA force fields.
• To assess the accuracy of RNA force fields in capturing native RNA-ligand interactions.

Main Methods:

• Utilized multicanonical MD simulations for dynamic docking of four RNA-ligand complexes.
• Analyzed 600 μs of simulation data, reweighted to the canonical ensemble at physiological temperature.
• Employed R-value analysis to measure native ligand-RNA contacts.

Main Results:

• Conformational ensembles varied across force fields for three of four targets.
• The parm99χOL3-vdW_bb force field showed the most accurate results based on R-value analysis.
• Identified overstabilization of non-native, closed RNA conformations by current force fields.

Conclusions:

• Current RNA force fields may inaccurately represent RNA-ligand interactions by favoring non-native states.
• Findings provide insights for developing improved RNA force fields for therapeutic development.
• Highlights the need to better assess non-native RNA conformations in simulations.