Polarizable force field for RNA based on the classical drude oscillator

Kuhr

et al. 2020

Preprint

Determination of RNA structural-dynamic properties is challenging for experimental methods. Thus atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments. However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the non-bonded ff terms. We have recently demonstrated that some improvement of state-of-the-art AMBER RNA ff can be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces the risk of side-effects. Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs). TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to over-fitting to A-form RNA. Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides. This allows to refine simulations of RNA TNs without affecting simulations of other RNAs. The approach is in line with adopted strategy of current RNA ffs, where the terminal nucleotides possess different parameters for the terminal atoms than the internal nucleotides. The combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations. TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed. Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with the primary NMR data which suggests that future tuning of some other ff terms might be useful.

Section: Introductionmentioning

confidence: 99%

Fine-tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides

Kuhr

et al. 2020

Preprint

“…A radical solution of the RNA ff problem could be the use of polarizable ffs. [18][19] However, their sophisticated parametrization not only results in extra computational cost but it yet remains to be seen if their accuracy will eventually surpass the best non-polarizable RNA ffs in extended simulations. Another option is to augment the existing ff forms by some additional simple ff terms that could be used to tune the ff performance while minimizing adverse side effects.…”

Section: Introductionmentioning

confidence: 99%

Improving The Performance Of The Amber Rna Force Field By Tuning The Hydrogen-Bonding Interactions

Zgarbová

et al. 2018

Preprint

# authors contributed equally * corresponding authors email: sponer@ncbr.muni.cz and pavel.banas@upol.cz KEYWORDS RNA, force field, MD simulation, enhanced sampling, folding, tetraloop.Recent studies generated large conformational ensembles of TNs 14-15, 17, 28-29, 31, 33-34 and TLs 14-15, 17, 28-29, 31, 35, 53-56 in order to assess the performance of RNA ffs. They showed that the available RNA ffs have persisting deficiencies causing, e.g., (i) shifts of the backbone dihedral angles to non-native values, (ii) problems with the c-dihedral angle distribution, and (iii) over-populated SPh and BPh hydrogen bond interactions. 15,25,55 Some of those studies also suggested potential directions for ff improvement, which included modifications of backbone dihedral terms, van der Waals (vdW) radii and charges, RNA interaction with solvent/ions (adjustments of Lennard-Jones parameters typically accompanied by modifications of the Lennard-Jones combining rules via nonbonded fix, NBfix, to balance the RNA-solvent interaction) and enforced distributions from solution experiments. 14, 17, 29-31, 53, 57-60 Computer folding of UNCG TLs appears to be much more challenging than folding of GNRA TLs and description of TNs, 15,35,53,55,61 as for the latter two systems some partial successes have been reported. Note that there have been repeated past claims in the literature about successful folding of RNA TLs in simulations. However, the claims were not confirmed by independent research groups, as extensively reviewed in Ref. 4 . The performance and possible shortcomings of another recently released ff 60 are discussed as part of this work.Previously, we have shown that at least two different imbalances likely contribute to the (in)correct folded/unfolded free-energy balance of TNs and TLs. The first problem was excessive stabilization of the unfolded ssRNA structure by intramolecular BPh and SPh interactions. 62 The excessive binding of 2'-hydroxyl groups (2'-OH) towards phosphate nonbridging oxygens (nbO) was reported earlier 27, 58 and could be partially reduced by using alternative phosphate oxygen parameters developed by Case et al. 63 in combination with the OPC 64 explicit solvent water model. 14 However, the OPC water model was shown to destabilize

“…Our data could serve as an important guidance for tuning of pair-additive as well as polarizable ffs. 92,93 However, when trying to design ff corrections based on this knowledge, we still could not get a decisive improvement. There could be several reasons for this.…”

Section: Discussionmentioning

confidence: 99%

UNCG RNA tetraloop as a formidable force-field challenge for MD simulations

Mráziková

et al. 2020

Preprint

Explicit solvent atomistic molecular dynamics (MD) simulations represent an established technique to study structural dynamics of RNA molecules and an important complement for diverse experimental methods. However, performance of molecular mechanical (MM) force fields (ffs) remains far from satisfactory even after decades of development, as apparent from a problematic structural description of some important RNA motifs. Actually, some of the smallest RNA molecules belong to the most challenging systems for MD simulations and, among them, the UNCG tetraloop is saliently difficult. We report a detailed analysis of UNCG MD simulations, depicting the sequence of events leading to the loss of the UNCG native state during MD simulations. We identify molecular interactions, backbone conformations and substates that are involved in the process. The total amount of MD simulation data analyzed in this work is close to 1.3 millisecond. Then, we unravel specific ff deficiencies using diverse quantum mechanical/molecular mechanical (QM/MM) and QM calculations. Comparison between the MM and QM methods shows discrepancies in the description of the 5’-flanking phosphate moiety and both signature sugar-base interactions. Our work indicates that poor behavior of the UNCG tetraloop in simulations is a complex issue that cannot be attributed to one dominant and straightforwardly correctable factor. Instead, there is a concerted effect of multiple ff inaccuracies that are coupled and amplifying each other. We attempted to improve the simulation behavior by some carefully-tailored interventions but the results are still far from satisfactory, underlying the difficulties in development of accurate nucleic acids ffs.