Biophysical Reviews

, Volume 4, Issue 3, pp 171–178 | Cite as

Insights into gene expression and packaging from computer simulations

  • Wilma K. Olson
  • Nicolas Clauvelin
  • Andrew V. Colasanti
  • Gautam Singh
  • Guohui Zheng


Within the nucleus of each cell lies DNA—an unfathomably long, twisted, and intricately coiled molecule—segments of which make up the genes that provide the instructions that a cell needs to operate. As we near the 60th anniversary of the discovery of the DNA double helix, crucial questions remain about how the physical arrangement of the DNA in cells affects how genes work. For example, how a cell stores the genetic information inside the nucleus is complicated by the necessity of maintaining accessibility to DNA for genetic processing. In order to gain insight into the roles played by various proteins in reading and compacting the genome, we have developed new methodologies to simulate the dynamic, three-dimensional structures of long, fluctuating, protein-decorated strands of DNA. Our a priori approach to the problem allows us to determine the effects of individual proteins and their chemical modifications on overall DNA structure and function. Here, we present our recent treatment of the communication between regulatory proteins attached to precisely constructed stretches of chromatin. Our simulations account for the enhancement in communication detected experimentally on chromatin compared to protein-free DNA of the same chain length, as well as the critical roles played by the cationic ‘tails’ of the histone proteins in this signaling. The states of chromatin captured in the simulations offer new insights into the ways that the DNA, histones, and regulatory proteins contribute to long-range communication along the genome.


Chromatin Histone tails DNA looping Monte-Carlo simulations Protein communication 



We thank Drs. Vasily Studitsky and Anirvan Sengupta for stimulating discussions and for sharing their findings, and Mr. Michael Smith for input on the presentation. The U.S. Public Health Service under research grant GM34809 and instrumentation grant RR022375 has generously supported this work.

Conflict of Interest



  1. Arya G, Schlick T (2006) Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model. Proc Natl Acad Sci USA 103:16236–16241CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chodaparambil JV, Barbera AJ, Lu X, Kaye KM, Hansen JC, Luger K (2007) A charged and contoured surface on the nucleosome regulates chromatin compaction. Nat Struct Mol Biol 14:1105–1107CrossRefPubMedPubMedCentralGoogle Scholar
  3. Czapla L, Swigon D, Olson WK (2006) Sequence-dependent effects in the cyclization of short DNA. J Chem Theor Comp 2:685–695. doi: 10.1021/ct060025+ CrossRefGoogle Scholar
  4. Czapla L, Swigon D, Olson WK (2008) Effects of the nucleoid protein HU on the structure, flexibility, and ring-closure properties of DNA deduced from Monte-Carlo simulations. J Mol Biol 382:353–370CrossRefPubMedPubMedCentralGoogle Scholar
  5. Czapla L, Peters JP, Rueter EM, Olson WK, Maher LJ III (2011) Understanding apparent DNA flexibility enhancement by HU and HMGB proteins: experiment and simulation. J Mol Biol 409:278–289CrossRefPubMedPubMedCentralGoogle Scholar
  6. Davey CA, Sargent DF, Luger K, Maeder AW, Richmond TJ (2002) Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J Mol Biol 319:1097–1113CrossRefPubMedGoogle Scholar
  7. De Carlo S, Chen B, Hoover TR, Kondrashkina E, Nogales E, Nixon T (2006) The structural basis for regulated assembly and function of the transcriptional activator NtrC. Genes Dev 20:1485–1495CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dickerson RE, Bansal M, Calladine CR, Diekmann S, Hunter WN, Kennard O, von Kitzing E, Lavery R, Nelson HCM, Olson WK, Saenger W, Shakked Z, Sklenar H, Soumpasis DM, Tung C-S, Wang AH-J, Zhurkin VB (1989) Definitions and nomenclature of nucleic acid structure parameters. J Mol Biol 208:787–791Google Scholar
  9. Dorigo B, Schalch T, Bystricky K, Richmond TJ (2003) Chromatin fiber folding: requirement for the histone H4 N-terminal tail. J Mol Biol 327:85–96CrossRefPubMedGoogle Scholar
  10. Flory PJ, Suter UW, Mutter M (1976) Macrocyclization equilibria. 1. Theory. J Am Chem Soc 98:5733–5739. doi: 10.1021/ja00435a001 CrossRefGoogle Scholar
  11. Jackson DA, Dickinson P, Cook PR (1990) The size of chromatin loops in HeLa cells. EMBO J 9:567–57PubMedPubMedCentralGoogle Scholar
  12. Jacobson H, Stockmayer WH (1950) Intramolecular reaction in polycondensations. I. The theory of linear systems. J Chem Phys 18:1600–1606. doi: 10.1063/1.1747547 Google Scholar
  13. Jensen MØ, Jogini V, Borhani DW, Leffler AE, Dror RO, Shaw DE (2012) Mechanism of voltage gating in potassium channels. Science 336:229–233CrossRefPubMedGoogle Scholar
  14. Kulaeva OI, Zheng G, Polikanov YS, Colasanti AV, Clauvelin N, Mukhopadhyay S, Sengupta AM, Studitsky VM, Olson WK (2012) Internucleosomal interactions mediated by histone tails allow distant communication in chromatin. J Biol Chem 287:20248–20257Google Scholar
  15. Langowski J (2006) Polymer chain models of DNA and chromatin. Eur Phys J E Soft Matter 19:241–249CrossRefPubMedGoogle Scholar
  16. Lu XJ, Olson WK (2003) 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res 31:5108–5121CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lu X-J, Olson WK (2008) 3DNA: a versatile, integrated software system for the analysis, rebuilding, and visualization of three-dimensional nucleic-acid structures. Nature Protoc 3:1213–1227CrossRefGoogle Scholar
  18. Manning GS (1978) The molecular theory of polyelectrolyte solutions with applications to the electrostatic properties of polynucleotides. Q Rev Biophys 11:179–246CrossRefPubMedGoogle Scholar
  19. Metropolis NA, Rosenbluth AW, Rosenbluth MN, Teller H, Teller E (1953) Equation of state calculations by fast computing machines. J Chem Phys 21:1087–1092. doi: 10.1063/1.1699114 Google Scholar
  20. Murakami KS, Masuda S, Darst SA (2002) Structural basis of transcription initiation: RNA polymerase holoenzyme at 4 Å resolution. Science 296:1280–1284CrossRefPubMedGoogle Scholar
  21. Olson WK, Gorin AA, Lu X-J, Hock LM, Zhurkin VB (1998) DNA sequence-dependent deformability deduced from protein-DNA crystal complexes. Proc Natl Acad Sci USA 95:11163–11168CrossRefPubMedPubMedCentralGoogle Scholar
  22. Polikanov YS, Studitsky VM (2009) Analysis of distant communication on defined chromatin templates in vitro. Methods Mol Biol 543:563–576CrossRefPubMedGoogle Scholar
  23. Polikanov YS, Rubtsov MA, Studitsky VM (2007) Biochemical analysis of enhancer-promoter communication in chromatin. Methods 41:250–258CrossRefPubMedPubMedCentralGoogle Scholar
  24. Ramakrishnan V (1997) Histone structure and the organization of the nucleosome. Annu Rev Biophys Biomol Struct 26:83–112. doi: 10.1146/annurev.biophys.26.1.83 CrossRefPubMedGoogle Scholar
  25. Rubtsov MA, Polikanov YS, Bondarenko VA, Wang YH, Studitsky VM (2006) Chromatin structure can strongly facilitate enhancer action over a distance. Proc Natl Acad Sci USA 103:17690–17695CrossRefPubMedPubMedCentralGoogle Scholar
  26. Sayle RA, Milnerwhite EJ (1995) RasMol: biomolecular graphics for all. Trends Biochem Sci 20:374–376CrossRefPubMedGoogle Scholar
  27. Schulz A, Langowski J, Rippe K (2000) The effect of the DNA conformation on the rate of NtrC-activated transcription of Escherichia coli RNA polymerase.σ54 holoenzyme. J Mol Biol 300:709–725CrossRefPubMedGoogle Scholar
  28. Shimada J, Yamakawa H (1984) Ring-closure probabilities for twisted wormlike chains. Application to DNA. Macromolecules 17:689–698. doi: 10.1021/ma00134a028 CrossRefGoogle Scholar
  29. Swigon D, Olson WK (2008) Mesoscale modeling of multi-protein-DNA assemblies: the role of the catabolic activator protein in Lac-repressor-mediated looping. Intl J Non-linear Mechanics 43:1082–1093. doi: 10.1016/j.ijnonlinmec.2008.07.003 Google Scholar
  30. Swigon D, Coleman BD, Olson WK (2006) Modeling the Lac repressor-operator assembly: the influence of DNA looping on Lac repressor conformation. Proc Natl Acad Sci USA 103:9879–9884CrossRefPubMedPubMedCentralGoogle Scholar
  31. Xu F, Olson WK (2010) DNA architecture, deformability, and nucleosome positioning. J Biomol Struct Dyn 27:725–739CrossRefPubMedPubMedCentralGoogle Scholar
  32. Zhou J, Fan JY, Rangasamy D, Tremethick DJ (2007) The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression. Nat Struct Mol Biol 14:1070–1076CrossRefPubMedGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer 2012

Authors and Affiliations

  • Wilma K. Olson
    • 1
  • Nicolas Clauvelin
    • 1
  • Andrew V. Colasanti
    • 1
  • Gautam Singh
    • 1
  • Guohui Zheng
    • 1
  1. 1.Rutgers, the State University of New JerseyPiscatawayUSA

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