Dynamics of the Protein Search for Targets on DNA in the Presence of Traps

Lange, Martin; Kochugaeva, Maria P.; Kolomeisky, Anatoly B.

doi:10.1021/acs.jpcb.5b07303

Cited by 25 publications

(53 citation statements)

References 36 publications

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“…Let us present several specific examples, although many more results have been obtained. [17][18][19][20][21][22][23][24][25][26][27][28][29] We start with the problem of how the presence of multiple target sites or multiple semi-specific trap sites affect the dynamics of the protein search.…”

Section: The Effect Of Multiple Targets and Trapsmentioning

confidence: 99%

“…For the two-target case the mean search times are averaged over all trajectories to both sites, while for the target and the trap system the mean search times are obtained only by considering the trajectories finishing at the target. 19 The results of calculations for the dynamic properties of the protein search in the presence of traps are presented in Figures 4 and 6. Again, three dynamic search phases are observed, but adding the trap generally facilitates the search dynamics, which is a counter-intuitive result: see Figure 4.…”

Section: The Effect Of Multiple Targets and Trapsmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Shvets¹,

Kochugaeva²,

Kolomeisky³

2018

Preprint

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Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity.

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Section: The Effect Of Multiple Targets and Trapsmentioning

confidence: 99%

Section: The Effect Of Multiple Targets and Trapsmentioning

confidence: 99%

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Shvets¹,

Kochugaeva²,

Kolomeisky³

2018

Preprint

Self Cite

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“…When a ~ 150 bp, then the bending of a DNA segment of size X0 into a circular loop requires 2 elastic 0 2 E a X π ~ 20-30 kBT. The average energy associated with the site-specific binding of TFs with CRMs (DBD1-S1 interactions) seems to be around - (15)(16)(17)(18)(19)(20) kBT (66) and the energy associated with the cumulative nonspecific interactions of all the DBD2s of TFs (~3n as in Eq. 12) will be around -(10-15) kBT.…”

Section: Feasibility Of the Propulsion Modelmentioning

confidence: 99%

Theory on the looping mediated directional-dependent propulsion of transcription factors along DNA

Murugan

2018

Preprint

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We show that the looping mediated transcription activation by the combinatorial transcription factors (TFs) can be achieved via directional-dependent propulsion, tethered sliding and tethered binding-sliding-unbinding modes. In the propulsion mode, the first arrived TF at the cis-regulatory motifs (CRMs) further recruits other TFs via protein-protein interactions. Such TFs complex has two different types of DNA binding domains (DBDs) viz. DBD1 which forms tight site-specific complex with CRMs via hydrogen bonding network and the promoter specific DBD2s which form nonspecific interactions around CRMs. When the sum of these specific and cumulative nonspecific interactions is sufficient, then the flanking DNA of CRMs will be bent into a circle over the TFs complex. The number of TFs involved in the combinatorial regulation plays critical role here. When the site-specific interactions and the cumulative nonspecific interactions are strong enough to resist the dissociation, then the sliding of DBD2s well within the Onsager radius associated with the DBD2s-DNA interface towards the promoter is the only possible way to release the elastic stress of the bent DNA. The DBD2s form tight synaptosome complex upon finding the promoter via sliding. When the number of TFs is not enough to bend the DNA in to a circle, then tethered sliding or tethered binding-sliding-unbinding modes are the possibilities. In tethered sliding, the CRMs-TFs complex forms nonspecific contacts with DNA via dynamic loops and then slide along DNA towards promoter without dissociation. In tethered binding-sliding-unbinding, the CRMs-TFs performs several cycles of nonspecific binding-sliding-unbinding before finding the promoter. Elastic and entropic energy barriers associated with the looping of DNA shape up the distribution of distances between CRMs and promoters. The combinatorial regulation of TFs in eukaryotes has evolved to overcome the looping energy barrier.

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“…Site specific binding of TFs with the genomic DNA seems to be influenced by several factors under in vivo conditions [9] viz. (a) conformational state of DNA [9,10] (b) spatial organization of various functionally related CRMs along the genomic DNA [11,12], (c) presence of other dynamic roadblock TF proteins and semi-stationary roadblocks such as nucleosomes especially in eukaryotes [13][14][15][16], (d) naturally occurring sequence traps on DNA [17,18], (e) conformational fluctuations in the DNA binding domains (DBDs) of TFs ( Fig. 1B) [19][20][21] and (f) the nonspecific electrostatic attractive forces and the counteracting shielding effects of other solvent ions and water molecules acting at the DNA-protein interface [22].…”

Section: Introductionmentioning

confidence: 99%

“…Here ζ is the distance between the position of nucleosome and location of TSS and TFBS on DNA. To include the effects of nucleosome occupancy pattern in the random walk simulations, we modified the value of the delay parameter ε of nucleosome at each simulation step in a position dependent manner such that the exact location of TSS and TFBS.The simulation results corresponding to the weighting function ( ) ερ ζ for k = 1 are shown in Figs.6A-B.With these settings, our simulation results suggest that the ε term in the expression for the MFPT that is given in Eqs 18. transform as ρε where ρ is the overall average of the nucleosome occupancy values around TSS and TFBS as defined in Eqs.…”

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confidence: 98%

Theory of site-specific DNA-protein interactions in the presence of nucleosome roadblocks

Murugan

2017

Preprint

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We show that nucleosomes can efficiently control the relative search times spent by transcription factors (TFs) on one-(1D) and three-dimensional (3D) diffusion routes towards locating their cognate sites on DNA. Our theoretical results suggest that the roadblock effects of nucleosomes are dependent on the relative position on DNA with respect to TFs and their cognate sites. Especially, nucleosomes exert maximum amount of hindrance to the 1D diffusion dynamics of TFs when they are positioned in between TFs and their cognate sites. The effective 1D diffusion coefficient (χTF) associated with the dynamics of TFs in the presence of nucleosome decreases with the free energy barrier (µ) associated the sliding dynamics of nucleosomes asSubsequently the mean first passage time (ηL) that is required by TFs to scan L number of binding sites on DNA via 1D diffusion increases with μ as ( ). When TFs move close to nucleosomes then they exhibit a typical sub-diffusive dynamics. Nucleosomes can enhance the search dynamics of TFs when TFs present in between nucleosomes and transcription factor binding sites (TFBS). The level of enhancement effects of nucleosomes seems to be much lesser than the level of retardation effects when nucleosomes present in between TFs and their cognate sites. These results suggest that nucleosome depleted regions around the cognate sites of TFs is mandatory for an efficient site-specific interactions of TFs with DNA. Remarkably the genome wide positioning pattern of TFs shows maximum at their specific binding sites and the positioning pattern of nucleosome shows minimum at the specific binding sites of TFs under in vivo conditions. This seems to be a consequence of increasing level of breathing dynamics of nucleosome cores and decreasing levels of fluctuations in the DNA binding domains of TFs as they move across TFBS. Since the extent of breathing dynamics of nucleosomes and fluctuations in the DBDs of TFs are directly linked with their respective 1D diffusion coefficients, the dynamics of TFs becomes slow as they approach their cognate sites so that TFs form tight site-specific complex. Whereas the dynamics of nucleosomes becomes rapid so that they pass through the cognate sites of TFs. Several in vivo datasets on genome wide positioning pattern of nucleosomes as well as TFs seem to agree well with our arguments. We further show that the condensed conformational state of DNA can significantly decrease the retarding effects of nucleosome roadblocks. The retarding effects of nucleosomes on the 1D diffusion dynamics of TFs can be nullified when the degree of condensation of the genomic DNA is such that it can permit a jump size associated with the dynamics of TFs beyond k > 150 bps.

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Dynamics of the Protein Search for Targets on DNA in the Presence of Traps

Cited by 25 publications

References 36 publications

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Theory on the looping mediated directional-dependent propulsion of transcription factors along DNA

Theory of site-specific DNA-protein interactions in the presence of nucleosome roadblocks

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