Nuclear Magnetic Resonance Spectra and AMBER OL3 and ROC-RNA Simulations of UCUCGU Reveal Force Field Strengths and Weaknesses for Single-Stranded RNA

Single-stranded regions of RNA are
important for folding of sequences
into 3D structures and for design of therapeutics targeting RNA. Prediction
of ensembles of 3D structures for single-stranded regions often involves
classical mechanical approximations of interactions defined by quantum
mechanical calculations on small model systems. Nuclear magnetic resonance
(NMR) spectra and molecular dynamics (MD) simulations of short single
strands provide tests for how well the approximations model many of
the interactions. Here, the NMR spectra for UCUCGU at 2, 15, and 30
°C are compared to simulations with the AMBER force fields, OL3
and ROC-RNA. This is the first such comparison to an oligoribonucleotide
containing an internal guanosine nucleotide (G). G is particularly
interesting because of its many H-bonding groups, large dipole moment,
and proclivity for both syn and anti conformations. Results reveal
formation of a G amino to phosphate non-bridging oxygen H-bond. The
results also demonstrate dramatic differences in details of the predicted
structures. The variations emphasize the dependence of predictions
on individual parameters and their balance with the rest of the force
field. The NMR data can serve as a benchmark for future force fields.