RNA force field with accuracy comparable to state-of-the-art protein force fields

Tan, Dazhi; Piana, Stefano; Dirks, Robert M.; Shaw, David E.

doi:10.1073/pnas.1713027115

Cited by 257 publications

(395 citation statements)

References 77 publications

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“…As part of our study, we tested the recently published ff by D. E. Shaw and co-workers. 60 We applied this ff for folding simulations of RNA TLs with short A-RNA stems as well as for standard simulations of selected RNA motifs. We observed major instabilities caused by this ff version in folded RNAs.…”

Section: Starting Structures and Simulation Setupmentioning

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

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: Starting Structures and Simulation Setupmentioning

confidence: 99%

“…4 . Another RNA ff modification (abbreviated as DESRES here) has been published recently, 60 reparametrizing the non-bonded as well as dihedral terms of the AMBER RNA ff and complementing the resulting parametrization with a specific water model. 109 We have tested this ff (see Supporting Information for full details) with the following results.…”

Section: Rest2mentioning

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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“…All these operations have been performed on an 8 CPU (Intel R Xeon R CPU E5-1620 3.50 GHz) Linux workstation. Molecular dynamics (MD) simulations were performed with an ACEMD engine (Harvey et al, 2009) on a GPU cluster composed of 18 NVIDIA drivers whose models go from GTX 980 to Titan V. For all the simulations, the ff14SB force field with χ modification tuned for RNA (χOL3) was adopted to describe ribonucleic acids, while a general Amber force field (GAFF) was adopted to parameterize small organic molecules (Wang et al, 2006;Sprenger et al, 2015;Tan et al, 2018).…”

Section: Software Overviewmentioning

confidence: 99%

Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?

2020

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Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy.

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“…Although simulation studies of the intact HBV capsid have shown that the inherent flexibility of some virus structures may limit the ability to obtain true atomic (1–2 ˚ A) resolution with cryo-EM [116], advances in image processing are enabling high-resolution asymmetric reconstructions capable of producing m o r e authentic descriptions of encapsidated genome, such as those obtained for the immature HBV particle and bacteriophage MS2 [142, 143]. The availability of more complete structural information, along with improved understanding of genome organization within capsids [144] and integrative modeling approaches [1] that employ increasingly accurate protein and nucleic acid force fields [145, 146], will support new simulation studies of all-atom virions in the near future, particularly for non-enveloped viruses.…”

Section: Toward All-atom Simulations Of Complete Virionsmentioning

confidence: 99%

All-atom virus simulations

Hadden

Perilla

2018

Current Opinion in Virology

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The constant threat of viral disease can be combated by the development of novel vaccines and therapeutics designed to disrupt key features of virus structure or infection cycle processes. Such development relies on high-resolution characterization of viruses and their dynamical behaviors, which are often challenging to obtain solely by experiment. In response, all-atom molecular dynamics simulations are widely leveraged to study the structural components of viruses, leading to some of the largest simulation endeavors undertaken to date. The present work reviews exemplary all-atom simulation work on viruses, as well as progress toward simulating entire virions.

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RNA force field with accuracy comparable to state-of-the-art protein force fields

Cited by 257 publications

References 77 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

Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?

All-atom virus simulations

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