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Modeling promoter search by E.coli RNA polymerase : One-dimensional diffusion in a sequence-dependent energy landscape Journal of Theoretical Biology 2009
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Introduction Gene Transcription: DNA → RNA
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Introduction Stages of transcription: 5’, 3’ RNA polymerase binding release mRNA
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Previous Work 1970: association rate much higher than the rate achievable by 3D diffusion. 1981: theory for 3D diffusion bind to DNA and then 1D diffusion on DNA(1D random walk) 1989: Two mode(search/recognition) of RNAP binding to DNA
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Previous Work 1999: RNAP searches its target site (the promoter) by randomly binding the DNA and subsequently sliding along (1D Brownian motion )DNA 2005: same probability(forward/backward) for 1D random walk is inefficient process But, a detailed understanding of one- dimensional diffusion and the possible sliding length could not yet be obtained.
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Previous Work Two kinds of sliding: 1D Brownian motion random walk sequence-dependent random walk Three Commonly discussed microscopic pathways for transferring a protein from one site to another. sliding hopping Intersegment transfer
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Preliminary assumption : the sliding process has a sequence-dependent component it does not perform a random walk with equal probabilities of stepping forward or backward the sliding is influenced by the binding energy at each position
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Preliminary transition rates : β=(k B T) -1 v affective attempt frequency k B the Boltzmann constant T the ambient temperature in Kelvin
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Preliminary Binding energy E(i p ) between the sigma factor and a promoter p at position i p :
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Preliminary
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Materials and Method Weight Matrix W the contribution of the 12 nucleotides in the promoter regions to the binding energy
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Materials and Method Weight Matrix W Color scheme: Black=A, dark gray=C, light gray=G, white=T.
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Materials and Method The binding energy E(i) at position i of an analyzed DNA sequence is obtained by minimizing the energy score calculated according to Eq. high negative overall energies should indicate candidate target sites
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Experiment Results Data: σ 70 and 651 promoters from RegulonDB Average energy landscape E(i)
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Experiment Results Speed of sliding : (τ i denotes the time the protein spends bound to site i ) Region 1: |g|=0 → r i = 2v. Region 2: |g|>0 → r i < 2v. Region 3: |g|>0 → r i < 2v. Region 4: |g|=0 → r i = 2v.
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Experiment Results Direction of sliding : (p i means forward ; q i means backward)
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Experiment Results Efficiency of promoter search : Mean first-passage time(MFPT) The mean number of steps the protein will make to slide from site i = 0 to site i = L (α i =q i /p i ) Assuming α 0 = α 1 = ….α k ( the approximation is a polynomial of order L depending on α )
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Experiment Results Efficiency of promoter search : L=50 (α i =q i /p i )
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Experiment Results Efficiency of promoter search : L=-50 (α i =q i /p i )
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Experiment Results
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Outline Introduction Previous Work Preliminary Materials and Method Experiment Results Discussion
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Discussion RNAP can move either direction L=50(5’→ 3’),in Region 2: MFPT decrease =more efficient L=-50(3’→ 5’),in Region 3: MFPT decrease =more efficient
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Discussion The decrease of binding energies the RNAP faces when approaching the promoters strongly influences the efficiency of promoter search.
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Discussion Summary the movement of the RNAP along the DNA slows down when approaching the promoter regions. sequence-dependent interaction between σ and promoter surrounding directs the RNAP towards the promoter. mean first-passage time decreases when approaching the promoter regions (promoter search becomes more efficient in this region)
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Discussion surrounding of the promoters contains important information to guide the RNAP and its sigma subunit. increasing the probability of transcription initiation by : slowing down the sliding process controlling the direction more efficiency of the movement.
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Problem Why like poisson? Do other species have the same distribution? Do all promoters have familiar energy landscape surrounding of the promoters?
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