Impact of 2′‐hydroxyl sampling on the conformational properties of RNA: Update of the CHARMM all‐atom additive force field for RNA

Abstract

Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick (WC) base pair opening which is not consistent with experiment while analysis of MD simulations show the 2′-hydroxyl moiety to almost exclusively sample the O3′ orientation. Quantum mechanical studies of RNA related model compounds indicate the energy minimum associated with the O3′ orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2′-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3′ orientations of the 2′-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR J-coupling values. Application of the model, designated CHARMM36, to a collection of canonical and non-canonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2′-hydroxyl moiety and support a model whereby the 2′-hydroxyl can enhance the probability of conformational transitions in RNA.

Nucleotide modifications and tRNA anticodon–mRNA codon interactions on the ribosome

“…S1, we compare the N1-N3 distance distribution of WC pairs in the stem of the tRNA anticodon arm for our simulations of the ASL free in solution and in the ribosome, using parameter sets CHARMM27 and CHARMM27d. Some base pair opening can be seen with CHARMM27, but it is significantly less common ((1%) than for the systems studied by Denning et al (2011), most likely because bases in the ribosomal environment are more confined than they are in free helices. Root mean square fluctuation (RMSF) data obtained with CHARMM27d (Supplemental Fig.…”

“…b Control simulation in larger sphere (34Å radius). CHARMM27d) resolves the problem (Denning et al 2011). In Supplemental Fig.…”

“…A tendency for local opening of Watson-Crick (WC) base pairs in simulations using the CHARMM27 force field has been observed and found to be due to oversampling of the O39 orientation of the 29-OH group of RNA (Denning et al 2011). This results in opening of z20% of the WC base pairs in a range of double helical RNA model systems, which is not consistent with the experiment.…”

“…The CHARMM27 all-hydrogen force field (MacKerell et al 1998;Foloppe and MacKerell 2000;MacKerell and Banavali 2000) was used in most simulations, and some test simulations were also run with the updated 29-hydroxyl parameters ''CHARMM27d'' (Denning et al 2011) in the CHARMM27 force field. The initial coordinates of the ribosome in complex with modified tRNA Val bound to mRNA with adenine, cytosine, uracil, and guanine in the third codon position were taken from X-ray structures with PDB ID 2UU9, 2UUA, 2UUB, and 2UUC, respectively (Weixlbaumer et al 2007).…”

“…Computer resources continue to grow, and with standard GNU/Linux PC clusters, we achieve 40-50 nsec/day for one of our typical systems with 8000 atoms when running eight jobs on eight cores each with CHARMM. In addition to these, one 56-nsec-long test simulation was run for each of the modified systems with the CHARMM27d parameters (Denning et al 2011).…”