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Long Time-Scale Atomistic Simulations of the Structure and Dynamics of Transcription Factor-DNA Recognition
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0002-2260-8493
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, 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 University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2019 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 17, p. 3576-3590Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2019. Vol. 123, no 17, p. 3576-3590
National Category
Physical Chemistry Biophysics
Identifiers
URN: urn:nbn:se:uu:diva-384077DOI: 10.1021/acs.jpcb.8b12363ISI: 000466989000003PubMedID: 30952192OAI: oai:DiVA.org:uu-384077DiVA, id: diva2:1318757
Funder
Swedish Research Council, 2016-06213Knut and Alice Wallenberg Foundation, KAW 2016.0077Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-05-28Bibliographically approved

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

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