A Fluctuating Density Energy Model for RNA Nucleobase Interactions

A new potential termed the Fluctuating Density (FD) model is presented as an alternative to traditional fixed partial-charge force fields for describing RNA nucleobase interactions within a molecular mechanics framework. Instead of atom-centered point charges, we take inspiration from fluctuating charge models and use a site-centered density representation for electron distributions to account for charge penetration effects present in both frozen and polarizable electrostatic interactions. A parameterization procedure is established to fit the FD model against energy decomposition analysis (EDA) for density functional theory (DFT) computations of both hydrogen-bonded and stacked RNA base pairs. Additionally, the FD model's ability to replicate intermolecular interactions of NMR resolved base pairs from the RSCB Protein Data Bank, as well as a comparison against the CHARMM Drude oscillator and AMOEBA force fields, is also presented. We find that charge penetration effects, when used as a cornerstone for parameterization, have strong influences on the remaining force field energy terms such as polarization and charge transfer. Furthermore, the FD model is able to produce polarization energetic contributions from electron density changes of similar magnitude as predicted by DFT computations.