Application of Computed FTIR Spectra of Nucleotide Monophosphates to RNA Force Field Refinement

We use the Hessian Matrix reconstruction (HMR) method to compute Fourier transform infrared (FTIR) spectra in the amide I region of nucleotide monophosphates solvated in TIP3P water and in OPC water from molecular dynamics simulations with the Amber OL3/OL15 force fields, and compare these to experimental spectra. The spectrum of TMP in TIP3P water fails to correctly capture the relative amplitudes of peaks in the amide I region when compared to experiment. Moreover, despite improvement in RNA conformations previously reported when using the OPC water model compared to TIP3P, the spectra of CMP and UMP solvated by OPC water model showed little resemblance to experimental spectra. Current van der Waals (vdW) parameters for RNA in the popular AMBER OL3/OL15 force fields were developed to reproduce neat liquid properties, while neglecting long-range electrostatic interactions, and have not undergone updates for several decades. Therefore, we varied the vdW radii of nucleic acid base amide O atoms to try to improve the FTIR spectra of TMP, CMP and UMP in OPC water. For all three pyrimidine monophosphates, we observed significant improvements in computed RNA spectra when the vdW radii of amide O were increased by 7.5%. We also confirmed that this change resulted in improved densities and enthalpies of solvation of three different solvents containing amide groups, as well as in improved simulated conformational equilibria of the r(CCCC) tetranucleotide. This result warrants future testing of the effect of our proposed force field modification on the accuracy of prediction of RNA conformational equilibria by molecular dynamics simulations employing the Amber OL3 force field.