Mixed double helices formed by RNA and DNA strands, commonly referred to as hybrid duplexes or hybrids, are essential in biological processes like transcription and reverse transcription. They are also important for their applications in CRISPR gene editing and nanotechnology. Yet, despite their significance, the hybrid duplexes have been seldom modeled by atomistic molecular dynamics methodology, and there is no benchmark study systematically assessing the force-field performance. Here, we present an extensive benchmark study of polypurine tract (PPT) and Dickerson-Drew dodecamer hybrid duplexes using contemporary and commonly utilized pairwise additive and polarizable nucleic acid force fields. Our findings indicate that none of the available force-field choices accurately reproduces all the characteristic structural details of the hybrid duplexes. The AMBER force fields are unable to populate the C3'-endo (north) pucker of the DNA strand and underestimate inclination. The CHARMM force field accurately describes the C3'-endo pucker and inclination but shows base pair instability. The polarizable force fields struggle with accurately reproducing the helical parameters. Some force-field combinations even demonstrate a discernible conflict between the RNA and DNA parameters. In this work, we offer a candid assessment of the force-field performance for mixed DNA/RNA duplexes. We provide guidance on selecting utilizable force-field combinations and also highlight potential pitfalls and best practices for obtaining optimal performance.

Czech Advanced Technology and Research Institute CATRIN Palacký University Křížkovského 511 8 Olomouc 779 00 Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 Brno 612 00 Czech Republic

IT4Innovations VSB Technical University of Ostrava 17 listopadu 2172 15 Ostrava Poruba 708 00 Czech Republic

Zobrazit více v PubMed

Sidorenkov I.; Komissarova N.; Kashlev M. Crucial Role of the RNA:DNA Hybrid in the Processivity of Transcription. Mol. Cell 1998, 2, 55–64. 10.1016/S1097-2765(00)80113-6. PubMed DOI

Telesnitsky A.; Goff S., Reverse Transcriptase and the Generation of Retroviral DNA. In Retroviruses, Coffin J.; Hughes S.; Varmus H., Eds. Cold Spring Harbor Laboratory Press: New York, 1997. PubMed

Anders C.; Niewoehner O.; Duerst A.; Jinek M. Structural Basis of PAM-dependent Target DNA Recognition by the Cas9 Endonuclease. Nature 2014, 513, 569–573. 10.1038/nature13579. PubMed DOI PMC

Jiang F.; Taylor D. W.; Chen J. S.; Kornfeld J. E.; Zhou K.; Thompson A. J.; Nogales E.; Doudna J. A. Structures of a CRISPR-Cas9 R-loop Complex Primed for DNA Cleavage. Science 2016, 351, 867–871. 10.1126/science.aad8282. PubMed DOI PMC

Afonin K. A.; Viard M.; Martins A. N.; Lockett S. J.; Maciag A. E.; Freed E. O.; Heldman E.; Jaeger L.; Blumenthal R.; Shapiro B. A. Activation of Different Split Functionalities on Re-association of RNA–DNA Hybrids. Nat. Nanotechnol. 2013, 8, 296–304. 10.1038/nnano.2013.44. PubMed DOI PMC

Ko S. H.; Su M.; Zhang C.; Ribbe A. E.; Jiang W.; Mao C. Synergistic Self-assembly of RNA and DNA Molecules. Nat. Chem. 2010, 2, 1050–1055. 10.1038/nchem.890. PubMed DOI PMC

Endo M.; Yamamoto S.; Tatsumi K.; Emura T.; Hidaka K.; Sugiyama H. RNA-templated DNA Origami Structures. Chem. Commun. 2013, 49, 2879–2881. 10.1039/c3cc38804b. PubMed DOI

Xiong Y.; Sundaralingam M. Crystal Structure of a DNA·RNA Hybrid Duplex with a Polypurine RNA r(gaagaagag) and a Complementary Polypyrimidine DNA d(CTCTTCTTC). Nucleic Acids Res. 2000, 28, 2171–2176. 10.1093/nar/28.10.2171. PubMed DOI PMC

Conn G. L.; Brown T.; Leonard G. A. The Crystal Structure of the RNA/DNA Hybrid r(GAAGAGAAGC)·d(GCTTCTCTTC) Shows Significant Differences to that Found in Solution. Nucleic Acids Res. 1999, 27, 555–561. 10.1093/nar/27.2.555. PubMed DOI PMC

Horton N. C.; Finzel B. C. The Structure of an RNA/DNA Hybrid: A Substrate of the Ribonuclease Activity of HIV-1 Reverse Transcriptase. J. Mol. Biol. 1996, 264, 521–533. 10.1006/jmbi.1996.0658. PubMed DOI

Han G. W.; Kopka M. L.; Langs D.; Sawaya M. R.; Dickerson R. E. Crystal Structure of an RNA·DNA Hybrid Reveals Intermolecular Intercalation: Dimer Formation by Base-pair Swapping. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 9214–9219. 10.1073/pnas.1533326100. PubMed DOI PMC

Drozdzal P.; Michalska K.; Kierzek R.; Lomozik L.; Jaskolski M. Structure of an RNA/DNA Dodecamer Corresponding to the HIV-1 Polypurine Tract at 1.6 A Resolution. Acta Crystallogr. D 2012, 68, 169–175. 10.1107/S0907444911053327. PubMed DOI

Kopka M. L.; Lavelle L.; Han G. W.; Ng H.-L.; Dickerson R. E. An Unusual Sugar Conformation in the Structure of an RNA/DNA Decamer of the Polypurine Tract May Affect Recognition by RNase H. J. Mol. Biol. 2003, 334, 653–665. 10.1016/j.jmb.2003.09.057. PubMed DOI

Gyi J. I.; Conn G. L.; Lane A. N.; Brown T. Comparison of the Thermodynamic Stabilities and Solution Conformations of DNA·RNA Hybrids Containing Purine-Rich and Pyrimidine-Rich Strands with DNA and RNA Duplexes. Biochemistry 1996, 35, 12538–12548. 10.1021/bi960948z. PubMed DOI

Salazar M.; Fedoroff O. Y.; Miller J. M.; Ribeiro N. S.; Reid B. R. The DNA strand in DNA.RNA hybrid duplexes is neither B-form nor A-form in solution. Biochemistry 1993, 32, 4207–4215. 10.1021/bi00067a007. PubMed DOI

Fedoroff O. Y.; Ge Y.; Reid B. R. Solution Structure of r(gaggacug):d(CAGTCCTC) Hybrid: Implications for the Initiation of HIV-1(+)-strand Synthesis. J. Mol. Biol. 1997, 269, 225–239. 10.1006/jmbi.1997.1024. PubMed DOI

Bachelin M.; Hessler G.; Kurz G.; Hacia J. G.; Dervan P. B.; Kessler H. Structure of a Stereoregular Phosphorothioate DNA/RNA Duplex. Nat. Struct. Biol. 1998, 5, 271–276. 10.1038/nsb0498-271. PubMed DOI

Fedoroff O. Y.; Salazar M.; Reid B. R. Structure of a DNA: RNA Hybrid Duplex: Why RNase H Does Not Cleave Pure RNA. J. Mol. Biol. 1993, 233, 509–523. 10.1006/jmbi.1993.1528. PubMed DOI

Hantz E.; Larue V.; Ladam P.; Le Moyec L.; Gouyette C.; Huynh Dinh T. Solution Conformation of an RNA–DNA Hybrid Duplex Containing a Pyrimidine RNA Strand and a Purine DNA Strand. Int. J. Biol. Macromol. 2001, 28, 273–284. 10.1016/S0141-8130(01)00123-4. PubMed DOI

Bondensgaard K.; Petersen M.; Singh S. K.; Rajwanshi V. K.; Kumar R.; Wengel J.; Jacobsen J. P. Structural Studies of LNA:RNA Duplexes by NMR: Conformations and Implications for RNase H Activity. Chem. – Eur. J. 2000, 6, 2687–2695. 10.1002/1521-3765(20000804)6:15<2687::AID-CHEM2687>3.0.CO;2-U. PubMed DOI

Banas P.; Hollas D.; Zgarbova M.; Jurecka P.; Orozco M.; Cheatham T. E.; Sponer J.; Otyepka M. Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins. J. Chem. Theory Comput. 2010, 6, 3836–3849. 10.1021/ct100481h. PubMed DOI PMC

Zgarbova M.; Otyepka M.; Sponer J.; Mladek A.; Banas P.; Cheatham T. E.; Jurecka P. Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles. J. Chem. Theory Comput 2011, 7, 2886–2902. 10.1021/ct200162x. PubMed DOI PMC

Šponer J.; Bussi G.; Krepl M.; Banáš P.; Bottaro S.; Cunha R. A.; Gil-Ley A.; Pinamonti G.; Poblete S.; Jurečka P.; et al. RNA Structural Dynamics as Captured by Molecular Simulations: A Comprehensive Overview. Chem. Rev. 2018, 118, 4177–4338. 10.1021/acs.chemrev.7b00427. PubMed DOI PMC

Zgarbová M.; Šponer J.; Jurečka P. Z-DNA as a Touchstone for Additive Empirical Force Fields and a Refinement of the Alpha/Gamma DNA Torsions for AMBER. J. Chem. Theory Comput. 2021, 17, 6292–6301. 10.1021/acs.jctc.1c00697. PubMed DOI

Tan D.; Piana S.; Dirks R. M.; Shaw D. E. RNA Force Field with Accuracy Comparable to State-of-the-art Protein Force Fields. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, E1346–E1355. 10.1073/pnas.1713027115. PubMed DOI PMC

Tucker M. R.; Piana S.; Tan D.; LeVine M. V.; Shaw D. E. Development of Force Field Parameters for the Simulation of Single- and Double-Stranded DNA Molecules and DNA–Protein Complexes. J. Phys. Chem. B 2022, 126, 4442–4457. 10.1021/acs.jpcb.1c10971. PubMed DOI PMC

Aytenfisu A. H.; Spasic A.; Grossfield A.; Stern H. A.; Mathews D. H. Revised RNA Dihedral Parameters for the Amber Force Field Improve RNA Molecular Dynamics. J. Chem. Theory Comput. 2017, 13, 900–915. 10.1021/acs.jctc.6b00870. PubMed DOI PMC

Ivani I.; Dans P. D.; Noy A.; Pérez A.; Faustino I.; Hospital A.; Walther J.; Andrio P.; Goñi R.; Balaceanu A.; et al. Parmbsc1: A Refined Force Field for DNA Simulations. Nat. Methods 2016, 13, 55–58. 10.1038/nmeth.3658. PubMed DOI PMC

Liebl K.; Zacharias M. Tumuc1: A New Accurate DNA Force Field Consistent with High-Level Quantum Chemistry. J. Chem. Theory Comput. 2021, 17, 7096–7105. 10.1021/acs.jctc.1c00682. PubMed DOI

Yildirim I.; Kennedy S. D.; Stern H. A.; Hart J. M.; Kierzek R.; Turner D. H. Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs. J. Chem. Theory Comput. 2012, 8, 172–181. 10.1021/ct200557r. PubMed DOI PMC

Yildirim I.; Stern H. A.; Tubbs J. D.; Kennedy S. D.; Turner D. H. Benchmarking AMBER Force Fields for RNA: Comparisons to NMR Spectra for Single-Stranded r(GACC) Are Improved by Revised chi Torsions. J. Phys. Chem. B 2011, 115, 9261–9270. 10.1021/jp2016006. PubMed DOI PMC

Bottaro S.; Bussi G.; Kennedy S. D.; Turner D. H.; Lindorff-Larsen K. Conformational Ensembles of RNA Oligonucleotides from Integrating NMR and Molecular Simulations. Sci. Adv. 2018, 4, eaar852110.1126/sciadv.aar8521. PubMed DOI PMC

Cesari A.; Gil-Ley A.; Bussi G. Combining Simulations and Solution Experiments as a Paradigm for RNA Force Field Refinement. J. Chem. Theory Comput. 2016, 12, 6192–6200. 10.1021/acs.jctc.6b00944. PubMed DOI

Chen J.; Liu H.; Cui X.; Li Z.; Chen H.-F. RNA-Specific Force Field Optimization with CMAP and Reweighting. J. Chem. Inf. Model. 2022, 62, 372–385. 10.1021/acs.jcim.1c01148. PubMed DOI

Liebl K.; Zacharias M. The Development of Nucleic Acids Force Fields: From an Unchallenged Past to a Competitive Future. Biophys. J. 2023, 122, 2841–2851. 10.1016/j.bpj.2022.12.022. PubMed DOI PMC

Dohnalová H.; Seifert M.; Matoušková E.; Klein M.; Papini F. S.; Lipfert J.; Dulin D.; Lankaš F. Temperature-Dependent Twist of Double-Stranded RNA Probed by Magnetic Tweezer Experiments and Molecular Dynamics Simulations. J. Phys. Chem. B 2024, 128, 664–675. 10.1021/acs.jpcb.3c06280. PubMed DOI PMC

Suresh G.; Priyakumar U. D. DNA–RNA Hybrid Duplexes with Decreasing Pyrimidine Content in the DNA Strand Provide Structural Snapshots for the A- to B-form Conformational Transition of Nucleic Acids. Phys. Chem. Chem. Phys. 2014, 16, 18148–18155. 10.1039/C4CP02478H. PubMed DOI

Suresh G.; Priyakumar U. D. Atomistic Details of the Molecular Recognition of DNA-RNA Hybrid Duplex by Ribonuclease H Enzyme. J. Chem. Sci. 2015, 127, 1701–1713. 10.1007/s12039-015-0942-7. DOI

Huang K.-W.; Wu C.-Y.; Toh S.-I.; Liu T.-C.; Tu C.-I.; Lin Y.-H.; Cheng A.-J.; Kao Y.-T.; Chu J.-W.; Hsiao Y.-Y. Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids. Nucleic Acids Res. 2023, 51, 11927–11940. 10.1093/nar/gkad910. PubMed DOI PMC

Fakharzadeh A.; Qu J.; Pan F.; Sagui C.; Roland C. Structure and Dynamics of DNA and RNA Double Helices Formed by d(CTG), d(GTC), r(CUG), and r(GUC) Trinucleotide Repeats and Associated DNA–RNA Hybrids. J. Phys. Chem. B 2023, 127, 7907–7924. 10.1021/acs.jpcb.3c03538. PubMed DOI PMC

Golyshev V. M.; Pyshnyi D. V.; Lomzov A. A. Calculation of Energy for RNA/RNA and DNA/RNA Duplex Formation by Molecular Dynamics Simulation. Mol. Biol. 2021, 55, 927–940. 10.1134/S002689332105006X. PubMed DOI

Liu J.-H.; Xi K.; Zhang X.; Bao L.; Zhang X.; Tan Z.-J. Structural Flexibility of DNA-RNA Hybrid Duplex: Stretching and Twist-Stretch Coupling. Biophys. J. 2019, 117, 74–86. 10.1016/j.bpj.2019.05.018. PubMed DOI PMC

Figiel M.; Krepl M.; Park S.; Poznański J.; Skowronek K.; Gołąb A.; Ha T.; Šponer J.; Nowotny M. Mechanism of Polypurine Tract Primer Generation by HIV-1 Reverse Transcriptase. J. Biol. Chem. 2018, 293, 191–202. 10.1074/jbc.M117.798256. PubMed DOI PMC

Figiel M.; Krepl M.; Poznański J.; Gołąb A.; Šponer J.; Nowotny M. Coordination between the Polymerase and RNase H Activity of HIV-1 Reverse Transcriptase. Nucleic Acids Res. 2017, 45, 3341–3352. 10.1093/nar/gkx004. PubMed DOI PMC

Wu J.; Ye W.; Yang J.; Chen H.-F. Conformational Selection and Induced Fit for RNA Polymerase and RNA/DNA Hybrid Backtracked Recognition. Front. Mol. Biosci. 2015, 2, 61.10.3389/fmolb.2015.00061. PubMed DOI PMC

Palermo G.; Miao Y.; Walker R. C.; Jinek M.; McCammon J. A. CRISPR-Cas9 Conformational Activation as Elucidated from Enhanced Molecular Simulations. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 7260–7265. 10.1073/pnas.1707645114. PubMed DOI PMC

Palermo G.; Miao Y.; Walker R. C.; Jinek M.; McCammon J. A. Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations. ACS Cent. Sci. 2016, 2, 756–763. 10.1021/acscentsci.6b00218. PubMed DOI PMC

Palermo G.; Casalino L.; Magistrato A.; Andrew McCammon J. Understanding the Mechanistic Basis of Non-coding RNA through Molecular Dynamics Simulations. J. Struct. Biol. 2019, 206, 267–279. 10.1016/j.jsb.2019.03.004. PubMed DOI PMC

Denning E. J.; Priyakumar U. D.; Nilsson L.; Mackerell A. D. Impact of 2’-Hydroxyl Sampling on the Conformational Properties of RNA: Update of the CHARMM All-Atom Additive Force Field for RNA. J. Comput. Chem. 2011, 32, 1929–1943. 10.1002/jcc.21777. PubMed DOI PMC

Hart K.; Foloppe N.; Baker C. M.; Denning E. J.; Nilsson L.; MacKerell A. D. Optimization of the CHARMM Additive Force Field for DNA: Improved Treatment of the BI/BII Conformational Equilibrium. J. Chem. Theory Comput. 2012, 8, 348–362. 10.1021/ct200723y. PubMed DOI PMC

Lemkul J. A.; MacKerell A. D. Jr. Polarizable Force Field for RNA Based on the Classical Drude Oscillator. J. Comput. Chem. 2018, 39, 2624–2646. 10.1002/jcc.25709. PubMed DOI PMC

Lemkul J. A.; MacKerell A. D. Polarizable Force Field for DNA Based on the Classical Drude Oscillator: I. Refinement Using Quantum Mechanical Base Stacking and Conformational Energetics. J. Chem. Theory Comput. 2017, 13, 2053–2071. 10.1021/acs.jctc.7b00067. PubMed DOI PMC

Lemkul J. A.; MacKerell A. D. Polarizable Force Field for DNA Based on the Classical Drude Oscillator: II. Microsecond Molecular Dynamics Simulations of Duplex DNA. J. Chem. Theory Comput. 2017, 13, 2072–2085. 10.1021/acs.jctc.7b00068. PubMed DOI PMC

Zhang C.; Lu C.; Jing Z.; Wu C.; Piquemal J.-P.; Ponder J. W.; Ren P. AMOEBA Polarizable Atomic Multipole Force Field for Nucleic Acids. J. Chem. Theory Comput. 2018, 14, 2084–2108. 10.1021/acs.jctc.7b01169. PubMed DOI PMC

Zhang C.; Bell D.; Harger M.; Ren P. Polarizable Multipole-Based Force Field for Aromatic Molecules and Nucleobases. J. Chem. Theory Comput. 2017, 13, 666–678. 10.1021/acs.jctc.6b00918. PubMed DOI PMC

Drew H. R.; Wing R. M.; Takano T.; Broka C.; Tanaka S.; Itakura K.; Dickerson R. E. Structure of a B-DNA Dodecamer: Conformation and Dynamics. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 2179–2183. 10.1073/pnas.78.4.2179. PubMed DOI PMC

Case D. A.; Aktulga H. M.; Belfon K.; Cerutti D. S.; Cisneros G. A.; Cruzeiro V. W. D.; Forouzesh N.; Giese T. J.; Götz A. W.; Gohlke H.; et al. AmberTools. J. Chem. Inf. Model. 2023, 63, 6183–6191. 10.1021/acs.jcim.3c01153. PubMed DOI PMC

Zgarbová M.; Šponer J.; Otyepka M.; Cheatham T. E.; Galindo-Murillo R.; Jurečka P. Refinement of the Sugar–Phosphate Backbone Torsion Beta for AMBER Force Fields Improves the Description of Z- and B-DNA. J. Chem. Theory Comput. 2015, 11, 5723–5736. 10.1021/acs.jctc.5b00716. PubMed DOI

Case D. A.; Aktulga H. M.; Belfon K.; Ben-Shalom I. Y.; Berryman J. T.; Brozell S. R.; Cerutti D. S.; Cheatham T. E. I.; Cisneros G. A.; Cruzeiro V. W. D.; et al., Amber 22. 2022.

Le Grand S.; Götz A. W.; Walker R. C. SPFP: Speed without Compromise—A Mixed Precision Model for GPU Accelerated Molecular Dynamics Simulations. Comput. Phys. Commun. 2013, 184, 374–380. 10.1016/j.cpc.2012.09.022. DOI

Krepl M.; Vögele J.; Kruse H.; Duchardt-Ferner E.; Wöhnert J.; Sponer J. An Intricate Balance of Hydrogen Bonding, Ion Atmosphere and Dynamics Facilitates a Seamless Uracil to Cytosine Substitution in the U-turn of the Neomycin-sensing Riboswitch. Nucleic Acids Res. 2018, 46, 6528–6543. 10.1093/nar/gky490. PubMed DOI PMC

Berendsen H. J. C.; Grigera J. R.; Straatsma T. P. The Missing Term in Effective Pair Potentials. J. Phys. Chem. 1987, 91, 6269–6271. 10.1021/j100308a038. DOI

Joung I. S.; Cheatham T. E. Determination of Alkali and Halide Monovalent Ion Parameters for Use in Explicitly Solvated Biomolecular Simulations. J. Phys. Chem. B 2008, 112, 9020–9041. 10.1021/jp8001614. PubMed DOI PMC

Ryckaert J. P.; Ciccotti G.; Berendsen H. J. C. Numerical-Integration of Cartesian Equations of Motion of a System with Constraints - Molecular-Dynamics of N-Alkanes. J. Comput. Phys. 1977, 23, 327–341. 10.1016/0021-9991(77)90098-5. DOI

Hopkins C. W.; Le Grand S.; Walker R. C.; Roitberg A. E. Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning. J. Chem. Theory Comput. 2015, 11, 1864–1874. 10.1021/ct5010406. PubMed DOI

Darden T.; York D.; Pedersen L. Particle mesh Ewald: An N ·log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, e1008910.1063/1.464397. DOI

Case D. A.; Aktulga H. M.; Belfon K.; Ben-Shalom I. Y.; Brozell S. R.; Cerutti D. S.; Cheatham T. E. I.; Cisneros G. A.; Cruzeiro V. W. D.; Darden T. A.; et al.AMBER 20, University of California: San Francisco, 2021.

Kuhrova P.; Best R.; Bottaro S.; Bussi G.; Sponer J.; Otyepka M.; Banas P. Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies. J. Chem. Theory Comput. 2016, 12, 4534–4548. 10.1021/acs.jctc.6b00300. PubMed DOI PMC

Zgarbova M.; Otyepka M.; Sponer J.; Lankas F.; Jurecka P. Base Pair Fraying in Molecular Dynamics Simulations of DNA and RNA. J. Chem. Theory Comput. 2014, 10, 3177–3189. 10.1021/ct500120v. PubMed DOI

Abraham M. J.; Murtola T.; Schulz R.; Páll S.; Smith J. C.; Hess B.; Lindahl E. GROMACS: High Performance Molecular Simulations Through Multi-level Parallelism from Laptops to Supercomputers. SoftwareX 2015, 1, 19–25. 10.1016/j.softx.2015.06.001. DOI

Piana S.; Donchev A. G.; Robustelli P.; Shaw D. E. Water Dispersion Interactions Strongly Influence Simulated Structural Properties of Disordered Protein States. J. Phys. Chem. B 2015, 119, 5113–5123. 10.1021/jp508971m. PubMed DOI

Tribello G. A.; Bonomi M.; Branduardi D.; Camilloni C.; Bussi G. PLUMED 2: New Feathers for an Old Bird. Comput. Phys. Commun. 2014, 185, 604–613. 10.1016/j.cpc.2013.09.018. DOI

Fröhlking T.; Mlýnský V.; Janeček M.; Kührová P.; Krepl M.; Banáš P.; Šponer J.; Bussi G. Automatic Learning of Hydrogen-bond Fixes in an AMBER RNA Force Field. J. Chem. Theory Comput. 2022, 18, 4490–4502. 10.1021/acs.jctc.2c00200. PubMed DOI PMC

Hess B.; Bekker H.; Berendsen H. J. C.; Fraaije J. G. E. M. LINCS: A Linear Constraint Solver for Molecular Simulations. J. Comput. Chem. 1997, 18, 1463–1472. 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H. DOI

Bussi G.; Donadio D.; Parrinello M. Canonical Sampling Through Velocity Rescaling. J. Chem. Phys. 2007, 126, 01410110.1063/1.2408420. PubMed DOI

Savelyev A.; MacKerell A. D. All-atom Polarizable Force Field for DNA Based on the Classical Drude Oscillator Model. J. Comput. Chem. 2014, 35, 1219–1239. 10.1002/jcc.23611. PubMed DOI PMC

Brooks B. R.; Brooks C. L.; Mackerell A. D.; Nilsson L.; Petrella R. J.; Roux B.; Won Y.; Archontis G.; Bartels C.; Boresch S.; et al. CHARMM: The Biomolecular Simulation Program. J. Comput. Chem. 2009, 30, 1545–1614. 10.1002/jcc.21287. PubMed DOI PMC

Lamoureux G.; Harder E.; Vorobyov I. V.; Roux B.; MacKerell A. D. A Polarizable Model of Water for Molecular Dynamics Simulations of Biomolecules. Chem. Phys. Lett. 2006, 418, 245–249. 10.1016/j.cplett.2005.10.135. DOI

Phillips J. C.; Hardy D. J.; Maia J. D. C.; Stone J. E.; Ribeiro J. V.; Bernardi R. C.; Buch R.; Fiorin G.; Hénin J.; Jiang W.; et al. Scalable Molecular Dynamics on CPU and GPU Architectures with NAMD. J. Chem. Phys. 2020, 153, 04413010.1063/5.0014475. PubMed DOI PMC

Kührová P.; Mlýnský V.; Otyepka M.; Šponer J.; Banáš P. Sensitivity of the RNA Structure to Ion Conditions as Probed by Molecular Dynamics Simulations of Common Canonical RNA Duplexes. J. Chem. Inf. Model. 2023, 63, 2133–2146. 10.1021/acs.jcim.2c01438. PubMed DOI PMC

Eastman P.; Swails J.; Chodera J. D.; McGibbon R. T.; Zhao Y.; Beauchamp K. A.; Wang L.-P.; Simmonett A. C.; Harrigan M. P.; Stern C. D.; et al. OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics. Plos Comput. Biol. 2017, 13, e100565910.1371/journal.pcbi.1005659. PubMed DOI PMC

Jiang W.; Hardy D. J.; Phillips J. C.; MacKerell A. D. Jr; Schulten K.; Roux B. High-Performance Scalable Molecular Dynamics Simulations of a Polarizable Force Field Based on Classical Drude Oscillators in NAMD. J. Phys. Chem. Lett. 2011, 2, 87–92. 10.1021/jz101461d. PubMed DOI PMC

Huang J.; Lemkul J. A.; Eastman P. K.; MacKerell A. D. Jr. Molecular Dynamics Simulations Using the Drude Polarizable Force Field on GPUs with OpenMM: Implementation, Validation, and Benchmarks. J. Comput. Chem. 2018, 39, 1682–1689. 10.1002/jcc.25339. PubMed DOI PMC

Chow K.-H.; Ferguson D. M. Isothermal-isobaric Molecular Dynamics Simulations with Monte Carlo Volume Sampling. Comput. Phys. Commun. 1995, 91, 283–289. 10.1016/0010-4655(95)00059-O. DOI

Miyamoto S.; Kollman P. A. Settle: An Analytical Version of the SHAKE and RATTLE Algorithm for Rigid Water Models. J. Comput. Chem. 1992, 13, 952–962. 10.1002/jcc.540130805. DOI

Essmann U.; Perera L.; Berkowitz M. L.; Darden T.; Lee H.; Pedersen L. G. A Smooth Particle Mesh Ewald Method. J. Chem. Phys. 1995, 103, 8577–8593. 10.1063/1.470117. DOI

Lagardère L.; Jolly L.-H.; Lipparini F.; Aviat F.; Stamm B.; Jing Z. F.; Harger M.; Torabifard H.; Cisneros G. A.; Schnieders M. J.; et al. Tinker-HP: A Massively Parallel Molecular Dynamics Package for Multiscale Simulations of Large Complex Systems with Advanced Point Dipole Polarizable Force Fields. Chemical Science 2018, 9, 956–972. 10.1039/C7SC04531J. PubMed DOI PMC

Roe D. R.; Cheatham T. E. PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J. Chem. Theory Comput. 2013, 9, 3084–3095. 10.1021/ct400341p. PubMed DOI

Humphrey W.; Dalke A.; Schulten K. VMD: Visual Molecular Dynamics. J. Mol. Graph. 1996, 14, 33–38. 10.1016/0263-7855(96)00018-5. PubMed DOI

Lu X.-J.; Olson W. K. 3DNA: A Software Package for the Analysis, Rebuilding and Visualization of Three-dimensional Nucleic Acid Structures. Nucleic Acids Res. 2003, 31, 5108–5121. 10.1093/nar/gkg680. PubMed DOI PMC

Babcock M. S.; Pednault E. P. D.; Olson W. K. Nucleic Acid Structure Analysis: Mathematics for Local Cartesian and Helical Structure Parameters That Are Truly Comparable Between Structures. J. Mol. Biol. 1994, 237, 125–156. 10.1006/jmbi.1994.1213. PubMed DOI

Olson W. K.; Bansal M.; Burley S. K.; Dickerson R. E.; Gerstein M.; Harvey S. C.; Heinemann U.; Lu X.-J.; Neidle S.; Shakked Z.; et al. A Standard Reference Frame for the Description of Nucleic Acid Base-pair Geometry. J. Mol. Biol. 2001, 313, 229–237. 10.1006/jmbi.2001.4987. PubMed DOI

Altona C.; Sundaral M. Conformational-Analysis of sugar ring in nucleosides and NUCLEOTIDES: New Description using concept of Pseudorotation. J. Am. Chem. Soc. 1972, 94, 8205.10.1021/ja00778a043. PubMed DOI

Li P.; Song L. F.; Merz K. M. Jr. Systematic Parameterization of Monovalent Ions Employing the Nonbonded Model. J. Chem. Theory Comput. 2015, 11, 1645–1657. 10.1021/ct500918t. PubMed DOI

Jurečka P.; Zgarbová M.; Černý F.; Salomon J. Multistate B- to A- Transition in Protein-DNA Binding – How Well is it Described by Current AMBER Force Fields?. J. Biomol. Struct. Dyn. 2024, 1–11. 10.1080/07391102.2024.2327539. PubMed DOI

Winkler L.; Galindo-Murillo R.; Cheatham T. E. III. Assessment of A- to B- DNA Transitions Utilizing the Drude Polarizable Force Field. J. Chem. Theory Comput. 2023, 19, 8955–8966. 10.1021/acs.jctc.3c01002. PubMed DOI PMC

Sarafianos S. G.; Das K.; Tantillo C.; Clark A. D.; Ding J.; Whitcomb J. M.; Boyer P. L.; Hughes S. H.; Arnold E. Crystal Structure of HIV-1 Reverse Transcriptase in Complex with a Polypurine Tract RNA:DNA. EMBO J. 2001, 20, 1449–1461. 10.1093/emboj/20.6.1449. PubMed DOI PMC

Bhattacharyya D.; Bansal M. Local Variability and Base Sequence Effects in DNA Crystal Structures. J. Biomol. Struct. Dyn. 1990, 8, 539–572. 10.1080/07391102.1990.10507828. PubMed DOI

Besseova I.; Banas P.; Kuhrova P.; Kosinova P.; Otyepka M.; Sponer J. Simulations of A-RNA Duplexes. The Effect of Sequence, Solute Force Field, Water Model, and Salt Concentration. J. Phys. Chem. B 2012, 116, 9899–9916. 10.1021/jp3014817. PubMed DOI

Waters J. T.; Lu X.-J.; Galindo-Murillo R.; Gumbart J. C.; Kim H. D.; Cheatham T. E. III; Harvey S. C. Transitions of Double-Stranded DNA Between the A- and B-Forms. J. Phys. Chem. B 2016, 120, 8449–8456. 10.1021/acs.jpcb.6b02155. PubMed DOI PMC

Winkler L.; Cheatham T. E. III. Benchmarking the Drude Polarizable Force Field Using the r(GACC) Tetranucleotide. J. Chem. Inf. Model. 2023, 63, 2505–2511. 10.1021/acs.jcim.3c00250. PubMed DOI PMC

Izadi S.; Anandakrishnan R.; Onufriev A. V. Building Water Models: A Different Approach. J. Phys. Chem. Lett. 2014, 5, 3863–3871. 10.1021/jz501780a. PubMed DOI PMC

Love O.; Galindo-Murillo R.; Zgarbová M.; Šponer J.; Jurečka P.; Cheatham T. E. III. Assessing the Current State of Amber Force Field Modifications for DNA–2023 Edition. J. Chem. Theory Comput. 2023, 19, 4299–4307. 10.1021/acs.jctc.3c00233. PubMed DOI PMC

Bergonzo C.; Cheatham T. E. Improved Force Field Parameters Lead to a Better Description of RNA Structure. J. Chem. Theory Comput. 2015, 11, 3969–3972. 10.1021/acs.jctc.5b00444. PubMed DOI

Havrila M.; Stadlbauer P.; Islam B.; Otyepka M.; Sponer J. Effect of Monovalent Ion Parameters on Molecular Dynamics Simulations of G-Quadruplexes. J. Chem. Theory Comput. 2017, 13, 3911–3926. 10.1021/acs.jctc.7b00257. PubMed DOI

Refinement of the Sugar Puckering Torsion Potential in the AMBER DNA Force Field