Conformational ensembles of RNA oligonucleotides from integrating NMR and molecular simulations

Bottaro, Sandro; Bussi, Giovanni; Kennedy, Scott D.; Turner, Douglas H.; Lindorff‐Larsen, Kresten

doi:10.1126/sciadv.aar8521

Cited by 119 publications

(221 citation statements)

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“…3 J scalar couplings were obtained from the Karplus relationships (see Supporting Information of the Ref. 33 for the details and experimental datasets). Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of the most populated structural clusters (in %) obtained from r(GACC) REST2 simulations at the reference replica (T = 298 K) with five variants of the gHBfix Experimental populations obtained by NMR refinement simulations25 and by reweighting extensive MD simulations based on these NMR data 33. c Present control cOL3CP simulation without any external potential (see Methods for the detailed setup).…”

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confidence: 99%

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

Kührová

Mlýnský

Zgarbová

et al. 2018

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# 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

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“…3 J scalar couplings were obtained from the Karplus relationships (see Supporting Information of the Ref. 33 for the details and experimental datasets). Figure 3).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Kührová

Mlýnský

Zgarbová

et al. 2018

Preprint

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“…Nevertheless, contemporary simulation methods and hardware already allow to obtain sufficiently converged simulation ensembles for TNs. 12,20,30 TN simulations can specifically monitor performance of ffs for several salient energy contributions, namely, (i) SPh and BPh interactions, (ii) base stacking interactions, (iii) backbone conformations and (iv) balance of these contributions with solvation. Experimental data shows that TNs mostly populate A-form conformations while MD simulations tend to significantly sample also non-native intercalated structures (or some other non-native structures, Figure 2) that are considered to be ff artifacts.…”

Section: Introductionmentioning

confidence: 99%

“…Experimental data shows that TNs mostly populate A-form conformations while MD simulations tend to significantly sample also non-native intercalated structures (or some other non-native structures, Figure 2) that are considered to be ff artifacts. 12,20,24,30 Obviously, when using TNs as a benchmark for ff refinement, one has to be concerned about a possible over-fitting of the ff towards the canonical A-RNA conformation (a potential problem of some recently published ffs 32 ), which may lead to side-effects for simulations of folded RNAs. 12,33 Here, we applied enhanced-sampling simulations to obtain conformational ensembles of five RNA tetranucleotides, i.e., r(AAAA), r(CAAU), r(CCCC), r(GACC), and r(UUUU).…”

Section: Introductionmentioning

confidence: 99%

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

Mlýnský

Kührová

Kuhr

et al. 2020

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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.

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“…S7). These findings indicate that both the helical and unfolded states of the peptides were sampled under these conditions, which is necessary for reweighting procedures to perform well 29 used the Cα and CO backbone chemical shifts to reweight the trajectories with a Bayesian/Maximum Entropy (BME) algorithm 30 . In this procedure the degree of reweighting and, therefore, the extent to which the backcalculated chemical shifts agree with those measured experimentally is controlled by the parameter θ, which determines the balance between the prior information encoded in the MD trajectory and the experimental data (Figs.…”

Section: Hydrogen Bonds Between Gln Side Chain Nh 2 Groups and Main Cmentioning

confidence: 99%

Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in the activation domain of a transcription factor

Escobedo¹,

Topal²,

Kunze³

et al. 2018

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Polyglutamine (polyQ) tracts are regions of low sequence complexity of variable lengthfound in more than one hundred human proteins. These tracts are frequent in activation domains of transcription factors and their length often correlates with transcriptional activity. In addition, in nine proteins, tract elongation beyond specific thresholds causes polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, here we addressed how the conformation of the polyQ tract of the androgen receptor (AR), a transcription factor associated with the polyQ disease spinobulbar muscular atrophy (SBMA), depends on its length. We found that the tract folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups. These bonds are bifurcate with the conventional main chain to main chain hydrogen bonds stabilizing αhelices. In addition, since tract elongation provides additional interactions, the helicity of the polyQ tract directly correlates with its length. These findings suggest a plausible rationale for the association between polyQ tract length and AR transcriptional activity and have implications for establishing the mechanistic basis of SBMA.Polyglutamine (polyQ) tracts are lowcomplexity regions that are composed almost exclusively of Gln residues. They are frequent in the human proteome, particularly in the intrinsically disordered domains of proteins involved in the regulation of transcription, such as the activation domains of transcription factors 1 . The biological function of polyQ tracts is not wellunderstood, but it has been suggested that they regulate the activity of the proteins that harbor them by modulating the stability of the complexes that they form 2 . The lengths of polyQ tracts are variable because their coding DNA sequences tend to adopt secondary structures that hamper replication and repair 3 . Contractions and expansions in polyQ tracts can have functional consequences, and the lengths of the tracts may have been subject to natural selection 4 . As an example, it has been proposed that the length of the polyQ tract present in the protein huntingtin correlates with the intellectual coefficient 5 , presumably because it plays important although still not welldefined roles in neural plasticity 6 .For nine specific proteins, the variability in the lengths of polyQ tracts has pathogenic implications. Expansions beyond given thresholds are associated with nine rare hereditary neurodegenerative diseases known as polyQ diseases 7 . The mechanistic basis of this phenomenon is a matter of debate. Some authors have proposed that the expanded transcripts themselves are the neurotoxic species 8 due to their propensity to phase separate 9 , while others have suggested that expanded polyQ proteins are inherently neurotoxic 10 . However, it is widely believed that polyQ expansions cause neurotoxicity because they decrease protein solubility, which in turn leads to the formation of...

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Conformational ensembles of RNA oligonucleotides from integrating NMR and molecular simulations

Abstract: Combining molecular simulations with NMR spectroscopy enables reconstruction of RNA tetranucleotide conformational ensembles.

Cited by 119 publications

References 50 publications

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

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

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

Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in the activation domain of a transcription factor

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