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Atomistic Molecular Dynamics Simulations of DNA in Complex 3D Arrangements for Comparison with Lower Resolution Structural Experiments

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Chromosome Architecture

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2476))

Abstract

Atomic-level computer simulations are a very useful tool for describing the structure and dynamics of complex biomolecules such as DNA and for providing detail at a resolution where experimental techniques cannot arrive. Molecular dynamics (MD) simulations of mechanically distorted DNA caused by agents like supercoiling and protein binding are computationally challenging due to the large size of the associated systems and timescales. However, nowadays they are achievable thanks to the efficient usage of GPU and to the improvements of continuum solvation models. This together with the concurrent improvements in the resolution of single-molecule experiments, such as atomic force microscopy (AFM), makes possible the convergence between the two. Here we present detailed protocols for doing so: for performing molecular dynamics (MD) simulations of DNA adopting complex three-dimensional arrangements and for comparing the outcome of the calculations with single-molecule experimental data with a lower resolution than atomic.

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References

  1. Noy A, Sutthibutpong T, Harris SA (2016) Protein/DNA interactions in complex DNA topologies: expect the unexpected. Biophys Rev 8:145–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fogg JM, Randall GL, Pettitt BM et al (2012) Bullied no more: when and how DNA shoves proteins around. Q Rev Biophys 45:257–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pyne ALB, Noy A, Main KHS et al (2021) Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides. Nat Commun 12:1–12

    Article  CAS  Google Scholar 

  4. Noy A, Maxwell A, Harris SA (2017) Interference between triplex and protein binding to distal sites on supercoiled DNA. Biophys J 112:523–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. D’Annessa I, Coletta A, Sutthibutpong T et al (2014) Simulations of DNA topoisomerase 1B bound to supercoiled DNA reveal changes in the flexibility pattern of the enzyme and a secondary protein-DNA binding site. Nucleic Acids Res 42:9304–9312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Dorman CJ (2019) DNA supercoiling and transcription in bacteria: a two-way street. BMC Mol Cell Biol. https://doi.org/10.1186/s12860-019-0211-6

  7. Lebrun A, Shakked Z, Lavery R (1997) Local DNA stretching mimics the distortion caused by the TATA box-binding protein. Proc Natl Acad Sci U S A 94:2993–2998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen Z, Yang H, Pavletich NP (2008) Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures. Nature 453:489–494

    Article  CAS  PubMed  Google Scholar 

  9. Shepherd JW, Greenall RJ, Probert MIJ et al (2020) The emergence of sequence-dependent structural motifs in stretched, torsionally constrained DNA. Nucleic Acids Res 48:1748–1763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. King GA, Gross P, Bockelmann U et al (2013) Revealing the competition between peeled ssDNA, melting bubbles, and S-DNA during DNA overstretching using fluorescence microscopy. Proc Natl Acad Sci U S A 110:3859–3864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zechiedrich EL, Khodursky AB, Bachellier S et al (2000) Roles of topoisomerases in maintaining steady-state DNA supercoiling in Escherichia coli. J Biol Chem 275:8103–8113

    Article  CAS  PubMed  Google Scholar 

  12. Sutthibutpong T, Matek C, Benham C et al (2016) Long-range correlations in the mechanics of small DNA circles under topological stress revealed by multi-scale simulation. Nucleic Acids Res 44:9121–9130

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Irobalieva RN, Fogg JM, Catanese DJ et al (2015) Structural diversity of supercoiled DNA. Nat Commun 6:8440

    Article  CAS  PubMed  Google Scholar 

  14. Matek C, Ouldridge TE, Doye JPK et al (2015) Plectoneme tip bubbles: coupled denaturation and writhing in supercoiled DNA. Sci Rep 5:7655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoshua S, Watson G, Howard J, et al (2020) A nucleoid-associated protein bends and bridges DNA in a multiplicity of topological states with varying specificity. bioRxiv. doi: https://doi.org/10.1101/2020.04.17.047076

  16. Sridhar A, Farr SE, Portella G et al (2020) Emergence of chromatin hierarchical loops from protein disorder and nucleosome asymmetry. Proc Natl Acad Sci U S A 117:7216–7224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Buckwalter JM, Norouzi D, Harutyunyan A et al (2017) Regulation of chromatin folding by conformational variations of nucleosome linker DNA. Nucleic Acids Res 45:9372–9387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Connolly M, Arra A, Zvoda V et al (2018) Static kinks or flexible hinges: multiple conformations of bent DNA bound to integration host factor revealed by fluorescence lifetime measurements. J Phys Chem B 122:11,519–11,534

    Article  CAS  Google Scholar 

  19. Jalal ASB, Tran NT, Stevenson CE et al (2020) Diversification of DNA-binding specificity by permissive and specificity-switching mutations in the ParB/Noc protein family. Cell Rep 32:107928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Doye JPK, Ouldridge TE, Louis AA, et al (2013) Coarse-graining DNA for simulations of DNA nanotechnology. https://pubs.rsc.org/en/content/articlehtml/2013/cp/c3cp53545b

  21. Fogg JM, Kolmakova N, Rees I et al (2006) Exploring writhe in supercoiled minicircle DNA. J Phys Condens Matter 18:S145–S159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shlyakhtenko LS, Potaman VN, Sinden RR et al (1998) Structure and dynamics of supercoil-stabilized DNA cruciforms. J Mol Biol 280:61–72

    Article  CAS  PubMed  Google Scholar 

  23. Schmatko T, Muller P, Maaloum M (2014) Surface charge effects on the 2D conformation of supercoiled DNA. Soft Matter 10:2520–2529

    Article  CAS  PubMed  Google Scholar 

  24. Lionberger TA, Demurtas D, Witz G et al (2011) Cooperative kinking at distant sites in mechanically stressed DNA. Nucleic Acids Res 39:9820–9832

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bednar J, Furrer P, Stasiak A et al (1994) The twist, writhe and overall shape of supercoiled DNA change during counterion-induced transition from a loosely to a tightly interwound superhelix possible implications for DNA structure in vivo. J Mol Biol 235:825–847

    Article  CAS  PubMed  Google Scholar 

  26. Amzallag A, Vaillant C, Jacob M et al (2006) 3D reconstruction and comparison of shapes of DNA minicircles observed by cryo-electron microscopy. Nucleic Acids Res 34:e125–e125

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sutthibutpong T, Noy A, Harris S (2016) Atomistic molecular dynamics simulations of DNA minicircle topoisomers: a practical guide to setup, performance, And analysis. Methods Mol Biol 1431:195–219

    Article  CAS  PubMed  Google Scholar 

  28. Nguyen H, Pérez A, Bermeo S et al (2015) Refinement of generalized born implicit solvation parameters for nucleic acids and their complexes with proteins. J Chem Theory Comput 11:3714–3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Perez A, MacCallum JL, Brini E et al (2015) Grid-based backbone correction to the ff12SB protein force field for implicit-solvent simulations. J Chem Theory Comput 11:4770–4779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nguyen H, Maier J, Huang H et al (2014) Folding simulations for proteins with diverse topologies are accessible in days with a physics-based force field and implicit solvent. J Am Chem Soc 136:13,959–13,962

    Article  CAS  Google Scholar 

  31. Sutthibutpong T, Harris SA, Noy A (2015) Comparison of molecular contours for measuring writhe in atomistic supercoiled DNA. J Chem Theory Comput 11:2768–2775

    Article  CAS  PubMed  Google Scholar 

  32. Velasco-Berrelleza V, Burman M, Shepherd JW et al (2020) SerraNA: a program to determine nucleic acids elasticity from simulation data. Phys Chem Chem Phys 22:19,254–19,266

    Article  CAS  Google Scholar 

  33. Chen J, Brooks CL (2008) Implicit modeling of nonpolar solvation for simulating protein folding and conformational transitions. Phys Chem Chem Phys 10:471–481

    Article  CAS  PubMed  Google Scholar 

  34. Gray A, Harlen OG, Harris SA et al (2015) In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation. Acta Crystallogr Sect D Biol Crystallogr 71:162–172

    Article  CAS  Google Scholar 

  35. Case DA, Cheatham TE, Darden T et al (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pronk S, Páll S, Schulz R et al (2013) GROMACS 45: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Phillips JC, Braun R, Wang W et al (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pérez A, Marchán I, Svozil D et al (2007) Refinement of the AMBER force field for nucleic acids: improving the description of α/γ conformers. Biophys J 92:3817–3829

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Krepl M, Zgarbová M, Stadlbauer P et al (2012) Reference simulations of noncanonical nucleic acids with different χ variants of the AMBER FORCE field: Quadruplex DNA, quadruplex RNA, and Z-DNA. J Chem Theory Comput 8:2506–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zgarbová M, Luque FJ, Šponer J et al (2013) Toward improved description of DNA backbone: revisiting epsilon and zeta torsion force field parameters. J Chem Theory Comput 9:2339–2354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Ivani I, Dans PD, Noy A et al (2015) Parmbsc1: a refined force field for DNA simulations. Nat Methods 13:55–58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Galindo-Murillo R, Robertson JC, Zgarbová M et al (2016) Assessing the current state of Amber force field modifications for DNA. J Chem Theory Comput 12:4114–4127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roe DR, Cheatham TE (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9:3084–3095

    Article  CAS  PubMed  Google Scholar 

  44. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  PubMed  Google Scholar 

  45. Lavery R, Moakher M, Maddocks JH et al (2009) Conformational analysis of nucleic acids revisited: Curves+. Nucleic Acids Res 37:5917–5929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lu XJ, Olson WK (2008) 3DNA: a versatile, integrated software system for the analysis, rebuilding and visualization of three-dimensional nucleic-acid structures. Nat Protoc 3:1213–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Noy A, Golestanian R (2012) Length scale dependence of DNA mechanical properties. Phys Rev Lett 109:228101

    Article  PubMed  CAS  Google Scholar 

  48. Tsui V, Case DA (2000) Theory and applications of the generalized born solvation model in macromolecular simulations. Biopolymers 56:275–291

    Article  CAS  PubMed  Google Scholar 

  49. Case DA, Betz RM, Cerutti DS, et al (2016) AMBER 2016. http://ambermd.org/

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Authors and Affiliations

  1. Department of Physics, University of York, Heslington, York, UK

    George Watson, Victor Velasco-Berrelleza & Agnes Noy

Authors
  1. George Watson
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  2. Victor Velasco-Berrelleza
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  3. Agnes Noy
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Corresponding author

Correspondence to Agnes Noy .

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Editors and Affiliations

  1. Departments of Physics and Biology, University of York, York, UK

    Mark C. Leake

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Watson, G., Velasco-Berrelleza, V., Noy, A. (2022). Atomistic Molecular Dynamics Simulations of DNA in Complex 3D Arrangements for Comparison with Lower Resolution Structural Experiments. In: Leake, M.C. (eds) Chromosome Architecture. Methods in Molecular Biology, vol 2476. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2221-6_8

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  • DOI: https://doi.org/10.1007/978-1-0716-2221-6_8

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2220-9

  • Online ISBN: 978-1-0716-2221-6

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