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Modeling and Simulation of Oligonucleotide Hybrids: Outlining a Strategy

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Book cover Oligonucleotide-Based Therapies

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2036))

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Abstract

Molecular dynamics simulations with a state-of-the-art force field provide an atomistic detailed description of the structural and thermodynamic features of biomolecules. Effects of chemical modifications and of the environment such as sequence, solvent, and ionic strength can explicitly be taken into account. Molecular simulation techniques can also provide insight in change in binding affinity, in protonation (pKa shift) and tautomeric propensity due to changes in the environment or in the molecular system. The quality and reliability of a simulation depend on the quality of the force field and on the reproducibility of the data, and validation depends on the availability of suitable experimental data. Here, we describe the workflow to investigate oligonucleotide hybrids using molecular simulation including hardware and software information.

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References

  1. Lundin KE, Gissberg O, Smith CIE (2015) Oligonucleotide therapies: the past and the present. Hum Gene Ther 26(8):475–485. https://doi.org/10.1089/hum.2015.070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kuhn H, Demidov VV, Nielsen PE, Frank-Kamenetskii MD (1999) An experimental study of mechanism and specificity of peptide nucleic acid (PNA) binding to duplex DNA 1 1Edited by I. Tinoco. J Mol Biol 286(5):1337–1345

    Article  CAS  PubMed  Google Scholar 

  3. Obika S, Nanbu D, Hari Y, Morio K-I, In Y, Ishida T, Imanishi T (1997) Synthesis of 2′-O, 4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C 3,-endo sugar puckering. Tetrahedron Lett 38(50):8735–8738. https://doi.org/10.1016/S0040-4039(97)10322-7

    Article  CAS  Google Scholar 

  4. Koshkin AA, Singh SK, Nielsen P, Rajwanshi VK, Kumar R, Meldgaard M, Olsen CE, Wengel J (1998) LNA (locked nucleic acids): synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron 54(14):3607–3630. https://doi.org/10.1016/S0040-4020(98)00094-5

    Article  CAS  Google Scholar 

  5. Lee JS, Woodsworth ML, Latimer LJ, Morgan AR (1984) Poly(pyrimidine). Poly(purine) synthetic DNAs containing 5-methylcytosine form stable triplexes at neutral pH. Nucleic Acids Res 12(16):6603–6614. https://doi.org/10.1093/nar/12.16.6603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ono A, Ts’o POP, Kan LS (1991) Triplex formation of oligonucleotides containing 2′-O-methylpseudoisocytidine in substitution for 2′-deoxycytidine. J Am Chem Soc 113:4032–4033. https://doi.org/10.1021/ja00010a077

    Article  CAS  Google Scholar 

  7. Sun B-W, Babu BR, Sørensen MD, Zakrzewska K, Wengel J, Sun J-S (2004) Sequence and pH effects of LNA-containing triple helix-forming oligonucleotides: physical chemistry, biochemistry, and modeling studies. Biochemistry 43(14):4160–4169. https://doi.org/10.1021/bi036064e

    Article  CAS  PubMed  Google Scholar 

  8. Petersen M, Bondensgaard K, Wengel J, Jacobsen JP (2002) Locked nucleic acid (LNA) recognition of RNA: NMR solution structures of LNA: RNA hybrids. J Am Chem Soc 124(21):5974–5982. https://doi.org/10.1021/ja012288d

    Article  CAS  PubMed  Google Scholar 

  9. Karplus M, Lavery R (2014) Significance of molecular dynamics simulations for life sciences. Isr J Chem 54(8–9):1042–1051. https://doi.org/10.1002/ijch.201400074

    Article  CAS  Google Scholar 

  10. Cheatham TE, Case DA (2013) Twenty-five years of nucleic acid simulations. Biopolymers 99(12):969–977. https://doi.org/10.1002/bip.22331

    Article  CAS  PubMed  Google Scholar 

  11. Pérez A, Luque FJ, Orozco M (2012) Frontiers in molecular dynamics simulations of DNA. Acc Chem Res 45(2):196–205. https://doi.org/10.1021/ar2001217

    Article  CAS  PubMed  Google Scholar 

  12. Foloppe N, Guéroult M, Hartmann B (2013) Simulating DNA by molecular dynamics: aims, methods, and validation. In: Monticelli L, Salonen E (eds) Biomolecular simulations: methods and protocols. Humana Press, Totowa, NJ, pp 445–468. https://doi.org/10.1007/978-1-62703-017-5_17

    Chapter  Google Scholar 

  13. Hartono YD, Xu Y, Karshikoff A, Nilsson L, Villa A (2018) Modeling pK shift in DNA triplexes containing locked nucleic acids. J Chem Inf Model 58(4):773–783. https://doi.org/10.1021/acs.jcim.7b00741

    Article  CAS  PubMed  Google Scholar 

  14. Pabon-Martinez YV, Xu Y, Villa A, Lundin KE, Geny S, Nguyen C-H, Pedersen EB, Jørgensen PT, Wengel J, Nilsson L, Smith CIE, Zain R (2017) LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures. Sci Rep 7(1):11043. https://doi.org/10.1038/s41598-017-09147-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yildirim I, Kierzek E, Kierzek R, Schatz GC (2014) Interplay of LNA and 2′-O-methyl RNA in the structure and thermodynamics of RNA hybrid systems: a molecular dynamics study using the revised AMBER force field and comparison with experimental results. J Phys Chem B 118(49):14177–14187. https://doi.org/10.1021/jp506703g

    Article  CAS  PubMed  Google Scholar 

  16. Suresh G, Priyakumar UD (2013) Structures, dynamics, and stabilities of fully modified locked nucleic acid (β-d-LNA and α-l-LNA) duplexes in comparison to pure DNA and RNA duplexes. J Phys Chem B 117(18):5556–5564. https://doi.org/10.1021/jp4016068

    Article  CAS  PubMed  Google Scholar 

  17. Suresh G, Priyakumar UD (2014) Atomistic investigation of the effect of incremental modification of deoxyribose sugars by locked nucleic acid (β-d-LNA and α-l-LNA) moieties on the structures and thermodynamics of DNA–RNA hybrid duplexes. J Phys Chem B 118(22):5853–5863. https://doi.org/10.1021/jp5014779

    Article  CAS  PubMed  Google Scholar 

  18. Xu Y, Villa A, Nilsson L (2017) The free energy of locking a ring: changing a deoxyribonucleoside to a locked nucleic acid. J Comput Chem 38(15):1147–1157. https://doi.org/10.1002/jcc.24692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Allnér O, Nilsson L (2011) Nucleotide modifications and tRNA anticodon-mRNA codon interactions on the ribosome. RNA 17(12):2177–2188. https://doi.org/10.1261/rna.029231.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Khandogin J, Brooks CL (2005) Constant pH molecular dynamics with proton tautomerism. Biophys J 89:141–157. https://doi.org/10.1529/biophysj.105.061341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goh GB, Knight JL, Brooks CL (2012) Constant pH molecular dynamics simulations of nucleic acids in explicit solvent. J Chem Theory Comput 8:36–46. https://doi.org/10.1021/ct2006314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wallace JA, Shen JK (2009) Predicting pKa values with continuous constant pH molecular dynamics. Methods Enzymol 466:455–475. https://doi.org/10.1016/S0076-6879(09)66019-5

    Article  CAS  PubMed  Google Scholar 

  23. Nilsson L, Karshikoff A (2011) Multiple pH regime molecular dynamics simulation for pK calculations. PLoS One 6(5):e20116. https://doi.org/10.1371/journal.pone.0020116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leach AR (2001) Molecular modeling: principles and applications, 2nd edn. Pearson Education Limited, London

    Google Scholar 

  25. Schlick T (2010) In: Antman SS, Marsden JE, Sirovich L (eds) Molecular modeling and simulation: an interdisciplinary guide, Interdisciplinary applied mathematics, vol 21. Springer, New York

    Chapter  Google Scholar 

  26. Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The AMBER biomolecular simulation programs. J Comput Chem 26(16):1668–1688. https://doi.org/10.1002/jcc.20290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brooks BR, Brooks CL 3rd, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30(10):1545–1614. https://doi.org/10.1002/jcc.21287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447. https://doi.org/10.1021/ct700301q

    Article  CAS  PubMed  Google Scholar 

  29. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1(2):19–25. https://doi.org/10.1016/j.softx.2015.06.001

    Article  Google Scholar 

  30. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26(16):1781–1802. https://doi.org/10.1002/jcc.20289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hart K, Foloppe N, Baker CM, Denning EJ, Nilsson L, MacKerell AD (2011) Optimization of the CHARMM additive force field for DNA: improved treatment of the BI/BII conformational equilibrium. J Chem Theory Comput 8(1):348–362. https://doi.org/10.1021/ct200723y

    Article  CAS  Google Scholar 

  32. Ivani I, Dans PD, Noy A, Perez A, Faustino I, Hospital A, Walther J, Andrio P, Goni R, Balaceanu A, Portella G, Battistini F, Gelpi JL, Gonzalez C, Vendruscolo M, Laughton CA, Harris SA, Case DA, Orozco M (2016) Parmbsc1: a refined force field for DNA simulations. Nat Methods 13(1):55–58. https://doi.org/10.1038/nmeth.3658

    Article  CAS  PubMed  Google Scholar 

  33. Zgarbová M, Šponer J, Otyepka M, Cheatham TE, Galindo-Murillo R, Jurečka P (2015) Refinement of the sugar–phosphate backbone torsion beta for AMBER force fields improves the description of Z- and B-DNA. J Chem Theory Comput 11(12):5723–5736. https://doi.org/10.1021/acs.jctc.5b00716

    Article  CAS  PubMed  Google Scholar 

  34. Galindo-Murillo R, Robertson JC, Zgarbová M, Šponer J, Otyepka M, Jurečka P, Cheatham TE (2016) Assessing the current state of Amber force field modifications for DNA. J Chem Theory Comput 12(8):4114–4127. https://doi.org/10.1021/acs.jctc.6b00186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dans PD, Ivani I, Hospital A, Portella G, González C, Orozco M (2017) How accurate are accurate force-fields for B-DNA? Nucleic Acids Res 45(7):4217–4230. https://doi.org/10.1093/nar/gkw1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ben Imeddourene A, Elbahnsi A, Guéroult M, Oguey C, Foloppe N, Hartmann B (2015) Simulations meet experiment to reveal new insights into DNA intrinsic mechanics. PLoS Comput Biol 11(12):e1004631. https://doi.org/10.1371/journal.pcbi.1004631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Aduri R, Psciuk BT, Saro P, Taniga H, Schlegel HB, SantaLucia J (2007) AMBER force field parameters for the naturally occurring modified nucleosides in RNA. J Chem Theory Comput 3(4):1464–1475. https://doi.org/10.1021/ct600329w

    Article  CAS  PubMed  Google Scholar 

  38. Xu Y, Vanommeslaeghe K, Aleksandrov A, MacKerell AD Jr, Nilsson L (2016) Additive CHARMM force field for naturally occurring modified ribonucleotides. J Comput Chem 37(10):896–912. https://doi.org/10.1002/jcc.24307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vanommeslaeghe K, MacKerell AD (2012) Automation of the CHARMM general force field (CGenFF) I: bond perception and atom typing. J Chem Inf Model 52(12):3144–3154. https://doi.org/10.1021/ci300363c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vanommeslaeghe K, Raman EP, MacKerell AD (2012) Automation of the CHARMM general force field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J Chem Inf Model 52(12):3155–3168. https://doi.org/10.1021/ci3003649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Savelyev A, MacKerell AD (2014) All- atom polarizable force field for DNA based on the classical Drude oscillator model. J Comput Chem 35(16):1219–1239. https://doi.org/10.1002/jcc.23611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926–935. https://doi.org/10.1063/1.445869

    Article  CAS  Google Scholar 

  43. Berendsen HJC, Grigera JR, Straatsma TP (1987) The missing term in effective pair potentials. J Phys Chem 91(24):6269–6271. https://doi.org/10.1021/j100308a038

    Article  CAS  Google Scholar 

  44. Allnér O, Nilsson L, Villa A (2012) Magnesium ion–water coordination and exchange in biomolecular simulations. J Chem Theory Comput 8:1493–1502. https://doi.org/10.1021/ct3000734

    Article  CAS  PubMed  Google Scholar 

  45. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242. https://doi.org/10.1093/nar/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Macke TJ, Case DA (1997) Modeling unusual nucleic acid structures. In: Molecular modeling of nucleic acids, vol 682. ACS symposium series, vol 682. American Chemical Society, pp 379–393. https://doi.org/10.1021/bk-1998-0682.ch024

    Google Scholar 

  47. Zheng GH, Lu XJ, Olson WK (2009) Web 3DNA-a web server for the analysis, reconstruction, and visualization of three-dimensional nucleic-acid structures. Nucleic Acids Res 37:W240–W246. https://doi.org/10.1093/Nar/Gkp358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical-integration of Cartesian equations of motion of a system with constraints - molecular-dynamics of N-alkanes. J Comput Phys 23(3):327–341. https://doi.org/10.1016/0021-9991(77)90098-5

    Article  CAS  Google Scholar 

  49. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1998) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18(12):1463–1472. https://doi.org/10.1002/(sici)1096-987x(199709)18:12<1463::aid-jcc4>3.0.co;2-h

    Article  Google Scholar 

  50. Lavery R, Moakher M, Maddocks JH, Petkeviciute D, Zakrzewska K (2009) Conformational analysis of nucleic acids revisited: curves+. Nucleic Acids Res 37(17):5917–5929. https://doi.org/10.1093/nar/gkp608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lu XJ, Olson WK (2003) 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res 31(17):5108–5121. https://doi.org/10.1093/nar/gkg680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pasi M, Zakrzewska K, Maddocks JH, Lavery R (2017) Analyzing DNA curvature and its impact on the ionic environment: application to molecular dynamics simulations of minicircles. Nucleic Acids Res 45(7):4269–4277. https://doi.org/10.1093/nar/gkx092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bennett CH (1976) Efficient estimation of free energy differences from Monte Carlo data. J Comput Phys 22:245–268. https://doi.org/10.1016/0021-9991(76)90078-4

    Article  Google Scholar 

  54. Bruckner S, Boresch S (2011) Efficiency of alchemical free energy simulations. I. A practical comparison of the exponential formula, thermodynamic integration, and Bennett’s acceptance ratio method. J Comput Chem 32(7):1303–1319. https://doi.org/10.1002/jcc.21713

    Article  CAS  PubMed  Google Scholar 

  55. Hartono YD, Pabon-Martinez YV, Uyar A, Wengel J, Lundin KE, Zain R, Smith CIE, Nilsson L, Villa A (2017) Role of pseudoisocytidine tautomerization in triplex-forming oligonucleotides: in silico and in vitro studies. ACS Omega 2(5):2165–2177. https://doi.org/10.1021/acsomega.7b00347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

    Lennart Nilsson & Alessandra Villa

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  1. Lennart Nilsson
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  2. Alessandra Villa
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Correspondence to Alessandra Villa .

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Editors and Affiliations

  1. Center for Advanced Therapies, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Olof Gissberg

  2. Center for Advanced Therapies, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Rula Zain

  3. Center for Advanced Therapies, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Karin E. Lundin

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Nilsson, L., Villa, A. (2019). Modeling and Simulation of Oligonucleotide Hybrids: Outlining a Strategy. In: Gissberg, O., Zain, R., Lundin, K. (eds) Oligonucleotide-Based Therapies. Methods in Molecular Biology, vol 2036. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9670-4_6

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  • DOI: https://doi.org/10.1007/978-1-4939-9670-4_6

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9669-8

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