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

Abstract

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.

MD simulations reveal the basis for dynamic assembly of Hfq–RNA complexes

“…Supporting information-This article contains supporting information (6,21,35,36,57,58,(70)(71)(72)(73)(74)(75)(76)(77) (Table S8).…”

Molecular Fluorophores Self-Organize into C-Dot Seeds and Incorporate into C-Dot Structures

“…Simulations were analyzed in terms of density profiles, the radius of gyration (R g ), number of hydrogen bonds (analyzed with GROMACS tools) and number of π-stacking interactions (evaluated with a home-written code, 66 Evolution of the number of hydrogen bonds between neutral IPCAs; Table S2: SAPT0 interaction energy decomposition for IPCA dimers; Figure S6: SAPT0 percentual contribution to the attractive interaction energy components; Table S3: MM and quantum mechanical calculations of stabilization and free energies of IPCA dimerization; Figure S7: Snapshots of MD simulations of IPCAs in solution performed under higher temperature and higher pressure;…”

Recognition of N6-methyladenosine by the YTHDC1 YTH domain studied by molecular dynamics and NMR spectroscopy: The role of hydration

“…Still, some of the NOE distance violations in our simulations occurred in vicinity of the G 2 and m 6 A 3 binding pockets (the primary interest of our study; see above). To verify our simulations and further improve the overall agreement with the experimental data, we tested a new approach termed the “NOEfix” potential (Figure 8), which is formally analogous to HBfix, gHBfix and tHBfix approaches tuning stability of H-bonds [40, 49, 61]. NOEfix introduces a mild stabilizing 1 kcal/mol energy bias between two hydrogens within interval of [ d ; d × 1.3] where d is experimental NOE upper bound.…”

“…For details of the technical implementation of the potential function, see Refs. [40, 49, 61]. NOEfix is a pragmatic means of introducing some bias based on the primary NMR data to compensate for the force-field deficiencies and to verify the performance of fully unbiased simulations while maintaining a wider range of conformations than what would be observed with traditional restraints where the energy penalty keeps increasing with distance.…”

“…To verify our simulations and further improve the overall agreement with the experimental data, we formulated and tested the "NOEfix" potential, which is formally analogous to HBfix, gHBfix and tHBfix approaches tuning stability of H-bonds. 41,[66][67] NOEfix introduces a mild stabilizing 1 kcal/mol energy bias between two hydrogens within interval of…”