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.


Supplementary material

Supporting Information: A Fluctuating Density Energy Model for RNA Nucleobase Interactions
In the supporting information, we provide details pertaining to the implementation of the DRESP charge fitting procedure and Connolly surface generation. We also include additional approximations made in the AmberFD model and a list of all parameters determined by the fitting procedure. Additionally, we include a partitioned list of PDB IDs and residues used in the EDA comparison between force fields, as well as additional violin plots of this analysis for each of the aforementioned PDB query criteria. We also include a secondary example of density differences in AmberFD and DFT for a small duplex simulation in solvent using AmberFD derived forces.