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The helical structure of DNA facilitates binding
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.ORCID-id: 0000-0002-6084-0197
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
2016 (Engelska)Ingår i: Journal of Physics A: Mathematical and Theoretical, ISSN 1751-8113, E-ISSN 1751-8121, Vol. 9, nr 36, artikel-id 364002Artikel i tidskrift (Övrigt vetenskapligt) Published
Abstract [en]

The helical structure of DNA imposes constraints on the rate of diffusion-limited protein binding. Here we solve the reaction-diffusion equations for DNA-like geometries and extend with simulations when necessary. We find that the helical structure can make binding to the DNA more than twice as fast compared to a case where DNA would be reactive only along one side. We also find that this rate advantage remains when the contributions from steric constraints and rotational diffusion of the DNA-binding protein are included. Furthermore, we find that the association rate is insensitive to changes in the steric constraints on the DNA in the helix geometry, while it is much more dependent on the steric constraints on the DNA-binding protein. We conclude that the helical structure of DNA facilitates the nonspecific binding of transcription factors and structural DNA-binding proteins in general.

Ort, förlag, år, upplaga, sidor
2016. Vol. 9, nr 36, artikel-id 364002
Nyckelord [en]
reaction-diffusion equation; steric constraints; helix geometry; diffusion limited
Nationell ämneskategori
Biofysik
Identifikatorer
URN: urn:nbn:se:uu:diva-263526DOI: 10.1088/1751-8113/49/36/364002ISI: 000383512000002OAI: oai:DiVA.org:uu-263526DiVA, id: diva2:858532
Forskningsfinansiär
EU, Europeiska forskningsrådetKnut och Alice Wallenbergs StiftelseTillgänglig från: 2015-10-02 Skapad: 2015-10-02 Senast uppdaterad: 2017-12-01Bibliografiskt 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

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