In silico direct folding of thrombin-binding aptamer G-quadruplex at all-atom level

Yang, Changwon; Kulkarni, Mandar; Lim, Manho; Pak, Youngshang

doi:10.1093/nar/gkx1079

Cited by 41 publications

(44 citation statements)

References 73 publications

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“…62 This suggests that the base-pairing interactions should be additionally stabilized, which is also consistent with several recent studies on DNA and RNA guanine quadruplexes and their folding intermediates stabilized by GG Hoogsteen base pairs. [92][93][94] In addition, the usefulness of stabilization of basebase H-bonds is also indicated by potentially excessive fraying of base-paired segments occasionally seen in MD simulations of folded RNAs. 4 In an attempt to fix the base-base interactions in a general fashion, i.e., to support both canonical and noncanonical base pairing, we added additional terms to the gHBfix potential, (Table 4).…”

Section: Resultsmentioning

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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# 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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Section: Resultsmentioning

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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“…It is advisable to keep in mind the limitations of the current approach. The quality of the results is expected to depend on the force field accuracy, and the binding of ions to sites deeply embedded in the structure (as it happens for instance in the case of DNA quadruplexes [49]) will probably require of slower pulling rates to allow a better exploration of the configurational space.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, ℰRMSD pulling starting from a random coil could generate folding pathways more realistic and contribute to a better understanding of the folding process [50]. It is interesting to observe that in a very recent paper ℰRMSD and RMSD from native were simultaneously used in order to drive folding of a DNA quadruplex [49]. Nucleotides are colored in green when the agreement is larger than 70%, yellow when it is between 30% and 70% and red otherwise.…”

Section: Discussionmentioning

confidence: 99%

Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered molecular dynamics

Poblete

Bottaro

Bussi

2018

Biochemical and Biophysical Research Communications

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Coarse-grained models can be of great help to address the problem of structure prediction in nucleic acids. On one hand they can make the prediction more efficient, while on the other hand they can also help to identify the essential degrees of freedom and interactions for the description of a number of structures. With the aim to provide an all-atom representation in an explicit solvent to the predictions of our SPlit and conQueR (SPQR) coarse-grained model of RNA, we recently introduced a backmapping procedure which enforces the predicted structure into an atomistic one by means of steered molecular dynamics. These simulations minimize the ERMSD, a particular metric which deals exclusively with the relative arrangement of nucleobases, between the atomistic representation and the target structure. In this paper, we explore the effects of this approach on the resulting interaction networks and backbone conformations by applying it on a set of fragments using as a target their native structure. We find that the geometry of the target structures can be reliably recovered, with limitations in the regions with unpaired bases such as bulges. In addition, we observe that the folding pathway can also change depending on the parameters used in the definition of the ERMSD and the use of other metrics such as the RMSD.

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Section: Scaling the Nucleobases Lj Parametersmentioning

confidence: 99%

“…A recent study from Pak and co-workers 58 suggests a correction to the LJ parameters of the nucleobase nitrogen and oxygen atoms: the vdW radii are scaled down by 2.5% for intramolecular interactions while keeping the unscaled parameters for nucleobase-solvent interactions. This approach, which reinforces base pairing, was successfully applied to fold the thrombin-binding DNA aptamer G-quadruplex, 58 and we might expect that the patch would be transferable to RNA. Focusing in the recalibration of p-stacking interactions, Chen and Garcia 41 modified heavy atom LJ parameters by a slight (5%) reduction in the vdW radii combined with a 20% and 10% reduction in the vdW well for nucleobase/nucleobase and nucleobase/water, respectively.…”

Section: Scaling the Nucleobases Lj Parametersmentioning

confidence: 99%

Modeling, Simulations, and Bioinformatics at the Service of RNA Structure

Dans

Gallego

Balaceanu

et al. 2019

Chem

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Although chemically close to DNA, RNA can adopt a wide range of structures from regular helices to complex globular conformations, showing a complexity similar to that of proteins. The determination of the structure of RNA molecules, crucial for functional understanding, is severely handicapped by their size and flexibility, which makes the systematic use of experimental approaches difficult. Simulation techniques are also suffering from very severe problems related to the accuracy of the methods and their ability to sample a large and complex conformational landscape. Here, we systematically review recent approaches created to reduce the shortcoming of the current generation of simulation methods-from highly accurate models able to deal with small systems to coarse-grained approaches that are less accurate but applicable to dealing with large models. WHAT HAVE WE LEARNED ABOUT RNA STRUCTURE FROM QM AND QM/MM METHODS?Physics teaches us that ab initio quantum mechanics (QM) can represent with high accuracy any biomolecular system, among them RNA. Unfortunately, because of their computational cost, the practical application of ab initio QM formalisms to large systems such as RNA is often impossible. In fact, even simpler QM methods such as those based on density functional theory (DFT) fail to treat systems larger than 10 2 atoms, several orders of magnitude less than the size required to study RNAs in solution. 1 Further simplifications of the basic QM formalism, such as those implicit in semiempirical (SE) methods, can extend the range of applicability of QM theory but at the expense of an expected loss of accuracy. 2 High-level QM and DFT calculations have had a central role in the development and validation of recent RNA force fields (FFs; see below). A recent example is the B97D3/AUG-CC-PVTZ study of the backbone and glycosidic torsions by Aytenfisu et al., 3 who highlighted systematic errors in current RNA FFs that might lead to incorrect molecular dynamics (MD) trajectories. Different conclusions were reached by the group led by Sponer, who again used DFT calculations as a reference, namely that the errors in current RNA FFs are related to imbalanced hydration and not to intrinsic errors in the classical gas phase Hamiltonian. 4 The same group recently studied 46 different backbone conformations of the UpU dinucleotide step (see Figure 1) by using a variety of QM methods from the state-of-the-art CCSD(T) to the latest-generation SE algorithms, 5 providing the community with an invaluable dataset for refinement of RNA FFs. Very recently our group used DFT/MM (density functional theory and molecular mechanics) calculations to fit some dihedrals directly for QM calculations in solution, opening a new approach to using DFT calculations in the refinement of RNA FF (see the next section). 6 The Bigger PictureRNAs are the ultimate frontier of structural biology. They are large and complex molecules that can adopt complex structures displaying a wide variety of functions from carriers of genetic information to regu...

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In silico direct folding of thrombin-binding aptamer G-quadruplex at all-atom level

Cited by 41 publications

References 73 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

Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered molecular dynamics

Modeling, Simulations, and Bioinformatics at the Service of RNA Structure

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