Empirical Corrections to the Amber RNA Force Field with Target Metadynamics

Abstract

The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics simulations. We here use experimental data collected from high-resolution X-ray structures to attempt an improvement of the latest version of the AMBER force field. A modified metadynamics algorithm is used to calculate correcting potentials designed to enforce experimental distributions of backbone torsion angles. Replica-exchange simulations of tetranucleotides including these correcting potentials show significantly better agreement with independent solution experiments for the oligonucleotides containing pyrimidine bases. Although the proposed corrections do not seem to be portable to generic RNA systems, the simulations revealed the importance of the α and ζ backbone angles for the modulation of the RNA conformational ensemble. The correction protocol presented here suggests a systematic procedure for force-field refinement.

Combining Simulations and Solution Experiments as a Paradigm for RNA Force Field Refinement

“…In a previous work 17 we have shown that on such systems a significant improvement of the agreement with NMR solution experiments can be obtained A,C 0.2010…”

“…For each force field, we evaluate the RMSE associated to scalar coupling as well as the number of violations and false positives in contacts predicted by nuclear Overhauser experiments (NOEs). NOEs are particularly important in tetranucleotides since they are sensitive to intercalated structures erroneously obtained using the Amber force field that have been previously reported [14][15][16][17] . We notice that NOEs might not be visible for many reasons others than the distance is too large.…”

Predicting the Kinetics of RNA Oligonucleotides Using Markov State Models

“…SI 14, SI 15). State #3 contains intercalated structures analogous to the one reported in previous works, 11,13,19,22,54 while state #0 presents A2 and A4 flipped out and stacked on each other. It is reasonable to expect other combinations of base orientation and stackings to arise when increasing the sampling.…”

“…We excluded from the calculations the contributions of the formation of intercalated/non-canonical structures, since the increased stability of such structures is a known limitation of the current force field. 11,13,19,22,54 This was done by using Eq. 4 and setting to zero the amplitudes, γ i , of the relative processes.…”

“…23 Hypothetically, a correction to the force field that fixes these problems might also affect the transition rates. However, corrections designed to penalize specific rotamers as those used in refs 22,23,57 are not expected to affect the transition rates between non-penalized metastable states. Moreover, once the force field has been refined so as to provide equilibrium populations in agreement with solution data, possible mismatches between the predicted time scales and the relaxation times observed in experiments might be used to identify errors in the parametrization of energetic barriers and suggest further refinements.…”