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Long Time-Scale Atomistic Simulations of the Structure and Dynamics of Transcription Factor-DNA Recognition
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.ORCID-id: 0000-0002-2260-8493
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. German Ctr Neurodegenerat Dis, Bioinformat Unit, Dept Epigenet & Syst Med Neurodegenerat Dis, Siebold Str 3A, D-37075 Gottingen, Germany.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
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2019 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, nr 17, s. 3576-3590Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Recent years have witnessed an explosion of interest in computational studies of DNA binding proteins, including both coarse grained and atomistic simulations of transcription factor-DNA recognition, to understand how these transcription factors recognize their binding sites on the DNA with such exquisite specificity. The present study performs microsecond time scale all-atom simulations of the dimeric form of the lactose repressor (Lad), both in the absence of any DNA and in the presence of both specific and nonspecific complexes, considering three different DNA sequences. We examine, specifically, the conformational differences between specific and nonspecific protein DNA interactions, as well as the behavior of the helix-turn-helix motif of Lad when interacting with the DNA. Our simulations suggest that stable Lad binding occurs primarily to bent A-form DNA, with a loss of Lad conformational entropy and optimization of correlated conformational equilibria across the protein. In addition, binding to the specific operator sequence involves a slightly larger number of stabilizing DNA protein hydrogen bonds (in comparison to nonspecific complexes), which may account for the experimentally observed specificity for this operator. In doing so, our simulations provide a detailed atomistic description of potential structural drivers for LacI selectivity.

Ort, förlag, år, upplaga, sidor
2019. Vol. 123, nr 17, s. 3576-3590
Nationell ämneskategori
Fysikalisk kemi Biofysik
Identifikatorer
URN: urn:nbn:se:uu:diva-384077DOI: 10.1021/acs.jpcb.8b12363ISI: 000466989000003PubMedID: 30952192OAI: oai:DiVA.org:uu-384077DiVA, id: diva2:1318757
Forskningsfinansiär
Vetenskapsrådet, 2016-06213Knut och Alice Wallenbergs Stiftelse, KAW 2016.0077Tillgänglig från: 2019-05-28 Skapad: 2019-05-28 Senast uppdaterad: 2020-01-30Bibliografiskt granskad
Ingår i avhandling
1. Modelling the Protein-DNA Interface
Öppna denna publikation i ny flik eller fönster >>Modelling the Protein-DNA Interface
2020 (Engelska)Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Protein-DNA interactions are crucial to life. Several millions of DNA base pair steps are organ- ised, read and protected by proteins in every cell. Protein-DNA interactions must be specific, controllable and reasonably fast. Understanding how these features coexist is one of the great challenges for biochemists and molecular biologists. Great interest has been directed towards the fast association rates measured for DNA-binding proteins such as bacterial transcription factors. These interactions have been described as proceeding by ‘facilitated diffusion’, which means that the non-specific interaction of a protein with DNA guides its way towards the target site. This can be studied using fluorescent labels and high resolution microscopes. This tech- niques can record traces of proteins, that diffuse along DNA until they bind their target sites and stop diffusion. But, which role the conformation of the protein or the DNA play a during the pro- cess of non-specific binding and recognition cannot be revealed. It is still unclear how proteins recognise their target sites. It is likely that conformational changes in both, the protein and in the DNA, play important roles. We can solve structures of protein-DNA complexes in molecular detail using crystallography or nuclear magnetic resonance. With all-atom molecular dynamic simulations we can elucidating their dynamics and obtain insights about conformational vari- ability. But some, large conformational changes and especially diffusion are processes that can be out of reach for the time-scales of normal all-atom simulations. Simplified representations of large biomolecules, so called coarse-grained models, can be used to study diffusion instead. The repressor of the lac operon is a well studied model system for understanding protein-DNA interactions. In this study, we applied coarse-grained simulations to define the search confor- mation of the protein, answering how it can sample the DNA effectively and how it recognises the target site sequence. Additionally we applied all-atom molecular dynamics to understand the stabilisation of the specific complex.

Ort, förlag, år, upplaga, sidor
Uppsala: Uppsala University, 2020. s. 62
Nyckelord
Protein-DNA interactions, Molecular Dynamics, Coarse-grained simulations, gene regulation
Nationell ämneskategori
Naturvetenskap
Forskningsämne
Biokemi
Identifikatorer
urn:nbn:se:uu:diva-403530 (URN)
Presentation
2020-03-13, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2020-02-19 Skapad: 2020-01-30 Senast uppdaterad: 2020-02-19Bibliografiskt granskad

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Liao, QinghuaLüking, MalinDeindl, SebastianElf, JohanKasson, Peter M.Kamerlin, Shina Caroline Lynn

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