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

Abstract

Recent computational efforts have shown that the current potential energy models used in molecular dynamics are not accurate enough to describe the conformational ensemble of RNA oligomers and suggest that molecular dynamics should be complemented with experimental data. We here propose a scheme based on the maximum entropy principle to combine simulations with bulk experiments. In the proposed scheme the noise arising from both the measurements and the forward models used to back calculate the experimental observables is explicitly taken into account. The method is tested on RNA nucleosides and is then used to construct chemically consistent corrections to the Amber RNA force field that allow a large set of experimental data on nucleosides and dinucleosides to be correctly reproduced. The transferability of these corrections is assessed against independent data on tetranucleotides and displays a previously unreported agreement with experiments. This procedure can be applied to enforce multiple experimental data on multiple systems in a self-consistent framework thus suggesting a new paradigm for force field refinement.

Predicting the Kinetics of RNA Oligonucleotides Using Markov State Models

“…We suggest that force field refinements should be mainly driven by comparison with equilibrium experiments in solution, as it has been done in a very recent work. 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.…”

“…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.…”

“…, refs. 10,11,13,18–23 ). MD was also used to characterize the stacking free energy associated with base fraying 24 and the stacking thermodynamics in DNA.…”

Coarse-Grained Directed Simulation

“…10 and { λ i } in Ref. 9, but differ by a constant factor $\left\{{\overline{f}}_i\right\}$ from { α i } in the EDS formulation in Refs. 8 and 11).…”

Mg2+ Binding Promotes SLV as a Scaffold in Varkud Satellite Ribozyme SLI-SLV Kissing Loop Junction

“…Despite known limitations in the energetic description of RNA systems (25), we can model ion association events (26, 27), refine RNA structures to better fit experimental data by including explicit solvation effects (28) and by empirical force field refinement (29), and decouple thermodynamic and kinetic properties of systems (20, 30). Additional work has focused on improving the representation of Mg 2+ ion energies and dynamics in fixed charge model simulations (31, 32, 33).…”