uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
MesoRD 1.0: Stochastic reaction-diffusion simulations in the microscopic limit
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
2012 (Engelska)Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, nr 23, s. 3155-3157Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

MesoRD is a tool for simulating stochastic reaction-diffusion systems as modeled by the reaction diffusion master equation. The simulated systems are defined in the Systems Biology Markup Language with additions to define compartment geometries. MesoRD 1.0 supports scale-dependent reaction rate constants and reactions between reactants in neighbouring subvolumes. These new features make it possible to construct physically consistent models of diffusion-controlled reactions also at fine spatial discretization.

Ort, förlag, år, upplaga, sidor
2012. Vol. 28, nr 23, s. 3155-3157
Nationell ämneskategori
Naturvetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-192453DOI: 10.1093/bioinformatics/bts584ISI: 000311902700025OAI: oai:DiVA.org:uu-192453DiVA, id: diva2:600157
Tillgänglig från: 2013-01-23 Skapad: 2013-01-21 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Reaction-Diffusion kinetics of Protein DNA Interactions
Öppna denna publikation i ny flik eller fönster >>Reaction-Diffusion kinetics of Protein DNA Interactions
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Transcription factors need to rapidly find one specific binding site among millions of nonspecific sites on the chromosomal DNA. In this thesis I use various aspects of reaction-diffusion theory to investigate the interaction between proteins and DNA and to explain the searching, finding and binding to specific operator sites. Using molecular dynamics methods we calculate the free energy profile for the model protein LacI as it leaves a nonspecific stretch of DNA and as it slides along DNA. Based on the free energy profiles we estimate the microscopic dissociation rate constant, kdmicro ~1.45×104s-1, and the 1D diffusion coefficient, D1 ~ 0.05-0.29 μm2s-1 (2-40μs to slide 1 basepair (bp)). At a non-atomistic level of detail we estimate the number of microscopic rebindings before a macroscopic dissociation occurs which leads to the  macroscopic residence time, τDmacro ~ 48±12ms resulting in a in vitro sliding length estimate of 135-345bp.

When we fit the DNA interaction parameters for in vivo conditions to recent single molecule in vivo experiments we conclude that neither hopping nor intersegment transfer contribute to the target search for the LacI dimer, that it appears to bind the specific Osym operator site as soon as it slides into it, and that the sliding length is around 40bp in the cell. The estimated in vivo D1 ~ 0.025 μm2s-1 is higher than expected from estimates of D1 based on viscosity and the atomistic simulations. Surprisingly, we were also forced to conclude that the nonspecific association for the LacI dimer appeared reaction limited which is in conflict with the free energy profile. This inconsistency is resolved by allowing for steric effects. Using reaction-diffusion theory and simulations we show that an apparent reaction limited association can be diffusion limited if geometry and steric effects are taken into account. Furthermore, the simulations show that a protein binds ~2 times faster to a DNA molecule with a helical reactive patch than to a stripe patch running along the length of the DNA. This facilitated binding has a direct impact on the search time especially in the presence of other DNA binding proteins.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1299
Nyckelord
umbrella sampling, molecular dynamics, RDME, PDE, sliding, intersegment transfer, hopping, sterics, intersegment transfer
Nationell ämneskategori
Biofysik Bioinformatik och systembiologi
Forskningsämne
Biologi med inriktning mot molekylär bioteknik
Identifikatorer
urn:nbn:se:uu:diva-263527 (URN)978-91-554-9360-8 (ISBN)
Externt samarbete:
Disputation
2015-11-06, C8:301, Husargatan 3, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-10-16 Skapad: 2015-10-02 Senast uppdaterad: 2016-09-09

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Fange, DavidMahmutovic, AnelElf, Johan

Sök vidare i DiVA

Av författaren/redaktören
Fange, DavidMahmutovic, AnelElf, Johan
Av organisationen
Beräknings- och systembiologiScience for Life Laboratory, SciLifeLab
I samma tidskrift
Bioinformatics
Naturvetenskap

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 448 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf