title: Increasing the efficiency of bacterial transcription simulations: when to exclude the genome without loss of accuracy.
abstract: BACKGROUND
  Simulating the major molecular events inside an Escherichia coli cell can lead to a very large number of reactions that compose its overall behaviour. Not only should the model be accurate, but it is imperative for the experimenter to create an efficient model to obtain the results in a timely fashion. Here, we show that for many parameter regimes, the effect of the host cell genome on the transcription of a gene from a plasmid-borne promoter is negligible, allowing one to simulate the system more efficiently by removing the computational load associated with representing the presence of the rest of the genome. The key parameter is the on-rate of RNAP binding to the promoter (k_on), and we compare the total number of transcripts produced from a plasmid vector generated as a function of this rate constant, for two versions of our gene expression model, one incorporating the host cell genome and one excluding it. By sweeping parameters, we identify the k_on range for which the difference between the genome and no-genome models drops below 5%, over a wide range of doubling times, mRNA degradation rates, plasmid copy numbers, and gene lengths.
  
  
  RESULTS
  We assess the effect of the simulating the presence of the genome over a four-dimensional parameter space, considering: 24 min<or=bacterial doubling time<or=100 min; 10<or=plasmid copy number<or=1000; 2 min<or=mRNA half-life<or=14 min; and 10 bp<or=gene length<or=10000 bp. A simple MATLAB user interface generates an interpolated k_on threshold for any point in this range; this rate can be compared to the ones used in other transcription studies to assess the need for including the genome.
  
  
  CONCLUSIONS
  Exclusion of the genome is shown to yield less than 5% difference in transcript numbers over wide ranges of values, and computational speed is improved by two to 24 times by excluding explicit representation of the genome.
authors.affiliation: Department of Chemical and Physical Sciences and Institute for Optical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N, Mississauga, ON, L5L 1C6, Canada. marco.iafolla@gmail.com
authors.forename: Marco A J
authors.initials: MA
authors.lastname: Iafolla
authors.forename: Guang Qiang
authors.initials: GQ
authors.lastname: Dong
authors.forename: David R
authors.initials: DR
authors.lastname: McMillen
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D002874:Chromosome Mapping / Q000379:methods*; D004926:Escherichia coli / Q000235:genetics*; D016680:Genome, Bacterial / Q000235:genetics*; D008969:Molecular Sequence Data; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2008 Feb;77(2 Pt 1):021919
references.pmid: 18352063
references.citation: Annu Rev Biophys Biomol Struct. 1998;27:59-75
references.pmid: 9646862
references.citation: Comput Biol Chem. 2004 Jul;28(3):165-78
references.pmid: 15261147
references.citation: Science. 1988 Sep 23;241(4873):1620-6
references.pmid: 17820893
references.citation: J Proteome Res. 2004 Mar-Apr;3(2):179-96
references.pmid: 15113093
references.citation: Prog Biophys Mol Biol. 2004 Jun-Jul;85(2-3):235-60
references.pmid: 15142746
references.citation: Bioessays. 2002 Dec;24(12):1110-7
references.pmid: 12447976
references.citation: Nature. 2004 Jan 29;427(6973):415-8
references.pmid: 14749823
references.citation: Biophys J. 2002 Oct;83(4):1891-901
references.pmid: 12324410
references.citation: Science. 2005 Sep 23;309(5743):2010-3
references.pmid: 16179466
references.citation: Biophys J. 2001 Dec;81(6):3116-36
references.pmid: 11720979
references.citation: J Bacteriol. 1999 Jan;181(1):197-203
references.pmid: 9864330
references.citation: J Phys Chem B. 2006 Nov 2;110(43):22019-28
references.pmid: 17064172
references.citation: OMICS. 2003 Winter;7(4):411-20
references.pmid: 14683613
references.citation: Science. 2002 Mar 1;295(5560):1662-4
references.pmid: 11872829
references.citation: In Silico Biol. 2004;4(3):293-309
references.pmid: 15724281
references.citation: Phys Biol. 2004 Dec;1(3-4):137-51
references.pmid: 16204833
references.citation: Nat Rev Genet. 2005 Jun;6(6):451-64
references.pmid: 15883588
references.citation: J R Soc Interface. 2006 Oct 22;3(10):603-16
references.pmid: 16971329
references.citation: Curr Opin Biotechnol. 2001 Dec;12(6):638-44
references.pmid: 11849948
references.citation: Nat Rev Genet. 2005 Jul;6(7):533-43
references.pmid: 15995697
references.citation: BMC Bioinformatics. 2004 Mar 08;5:24
references.pmid: 15113411
references.citation: Nature. 2002 Nov 14;420(6912):224-30
references.pmid: 12432407
references.citation: C R Biol. 2003 Oct-Nov;326(10-11):879-92
references.pmid: 14744094
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8614-9
references.pmid: 11438714
references.citation: Phys Rev Lett. 2006 Mar 10;96(9):098102
references.pmid: 16606319
references.citation: Annu Rev Biomed Eng. 2003;5:179-206
references.pmid: 14527313
references.citation: Science. 2005 Mar 25;307(5717):1965-9
references.pmid: 15790857
references.citation: Biotechnol Bioeng. 1991 Apr 5;37(8):736-45
references.pmid: 18600670
references.citation: Q Rev Biophys. 2001 Feb;34(1):1-59
references.pmid: 11388089
references.citation: Trends Biochem Sci. 2001 Oct;26(10):597-604
references.pmid: 11590012
references.citation: PLoS Biol. 2004 Jun;2(6):e137
references.pmid: 15124029
references.citation: Nat Genet. 2006 Jun;38(6):610-1
references.pmid: 16736013
references.citation: Nat Genet. 2006 Jun;38(6):636-43
references.pmid: 16715097
references.citation: Science. 2002 Aug 16;297(5584):1183-6
references.pmid: 12183631
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D293-5
references.pmid: 14681416
references.citation: Chaos. 2006 Jun;16(2):026101
references.pmid: 16822033
references.citation: Nature. 2003 Apr 10;422(6932):633-7
references.pmid: 12687005
references.citation: Nature. 2006 Feb 16;439(7078):861-4
references.pmid: 16372021
references.citation: Annu Rev Genomics Hum Genet. 2001;2:343-72
references.pmid: 11701654
references.citation: Nat Rev Genet. 2001 Apr;2(4):268-79
references.pmid: 11283699
references.citation: Curr Opin Biotechnol. 2006 Oct;17(5):548-57
references.pmid: 16978856
references.citation: Nature. 1976 Aug 5;262(5568):467-71
references.pmid: 958399
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10555-60
references.pmid: 12145321
references.citation: Nature. 1969 Dec 6;224(5223):957-64
references.pmid: 5360547
references.citation: Biophys J. 2006 Aug 15;91(4):1235-47
references.pmid: 16714341
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12795-800
references.pmid: 12237400
references.citation: Mol Syst Biol. 2006;2:41
references.pmid: 16883354
references.citation: Nature. 2002 Nov 14;420(6912):206-10
references.pmid: 12432404
references.citation: PLoS Biol. 2004 Dec;2(12):e412
references.pmid: 15562315