Accurate Modeling of RNA Hairpins Through the Explicit Treatment of Electronic Polarizability with the Classical Drude Oscillator Force Field

Abstract

Molecular dynamics (MD) simulations play a crucial role in modeling biomolecular systems in which the electrostatic interactions are critical in dictating the structural and dynamical properties. Thus, the treatment of the electrostatic interactions defined in the underlying force field (FF) strongly affects the simulation accuracy. Most FFs use fixed partial atomic charges to include electrostatic interactions, and therefore lack the electronic polarization response, representing an intrinsic limitation. To address this limitation, polarizable FFs have been developed that treat atomic polarizabilities explicitly. Here we present the application of the all-atom polarizable (Drude) and non-polarizable (CHARMM) nucleic acid FFs in RNA hairpin systems to investigate the impact of polarization on structural properties, dipole moment distributions, and cation interactions. Results show that the presence of polarizability in the FF significantly improves the stabilization of RNA hairpin structure. As expected, the distributions of dipole moments show more fluctuations when simulated using the polarizable FF, with the variation in dipoles contributing to the stabilization of the structures of the loop regions of the RNAs. Contact map analyses between the bases and cations show that the variation of the ion distribution around the entire hairpin is larger for the polarizable FF and the cations occupy the outer hydration shell to a greater extent. The presented results indicate the importance of the explicit treatment of electronic polarizability in molecular simulations of RNA, including in non-canonical regions.