Please, get in my way so that I can be more efficient!

The article by Marcovitz and Levy explores, using computer simulations, how obstacles facilitate DNA search by proteins (1xObstacles may facilitate and direct DNA search by proteins. Marcovitz, A. and Levy, Y. Biophys. J. 2013; 104: 2042–2050Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all References1). The observation that Lac repressor could find its preferred DNA binding site two orders-of-magnitude faster than expected from three-dimensional diffusion through solution was first made in the 1970s (2xThe Lac repressor-operator interaction. 3. Kinetic studies. Riggs, A.D., Bourgeois, S., and Cohn, M. J. Mol. Biol. 1970; 53: 401–417Crossref | PubMed | Scopus (451)See all References, 3xDiffusion controlled reaction rates in spheroidal geometry. Application to repressor-operator association and membrane bound enzymes. Richter, P.H. and Eigen, M. Biophys. Chem. 1974; 2: 255–263Crossref | PubMed | Scopus (193)See all References). Berg et al. (4xDiffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. Berg, O.G., Winter, R.B., and von Hippel, P.H. Biochemistry. 1981; 20: 6929–6948Crossref | PubMedSee all References4) developed the theory that explained this rapid search in terms of a combination three-dimensional diffusion and sliding of the protein along the DNA chain. This theory is well accepted by the scientific community, but single molecule experiments have added a few caveats to the story, like the role of obstacles in the search (5xTowards a molecular view of transcriptional control. Zakrzewska, K. and Lavery, R. Curr. Opin. Struct. Biol. 2012; 22: 160–167Crossref | PubMed | Scopus (16)See all References, 6xVisualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice. Gorman, J., Plys, A.J...., and Greene, E.C. Nat. Struct. Mol. Biol. 2010; 17: 932–938Crossref | PubMed | Scopus (93)See all References, 7xSingle-molecule imaging reveals target-search mechanisms during DNA mismatch repair. Gorman, J., Wang, F...., and Greene, E. Proc. Natl. Acad. Sci. USA. 2012; 109: E3074–E3083Crossref | PubMed | Scopus (63)See all References, 8xAn end to 40 years of mistakes in DNA-protein association kinetics?. Halford, S.E. Biochem. Soc. Trans. 2009; 37: 343–348Crossref | PubMed | Scopus (115)See all References). For example, Gorman et al. (6xVisualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice. Gorman, J., Plys, A.J...., and Greene, E.C. Nat. Struct. Mol. Biol. 2010; 17: 932–938Crossref | PubMed | Scopus (93)See all References6) showed that protein diffusion along the one-dimensional DNA chain in chromosomes uses a hopping/stepping mechanism that readily bypasses stationary obstacles.Halford (8xAn end to 40 years of mistakes in DNA-protein association kinetics?. Halford, S.E. Biochem. Soc. Trans. 2009; 37: 343–348Crossref | PubMed | Scopus (115)See all References8) has argued that the enhanced search is due to electrostatics and that reduced dimensionality reduces the rate of target site location. Halford (8xAn end to 40 years of mistakes in DNA-protein association kinetics?. Halford, S.E. Biochem. Soc. Trans. 2009; 37: 343–348Crossref | PubMed | Scopus (115)See all References8) has also argued that one-dimensional diffusion is limited to regions of nearly 50 basepairs around each landing site. Taken together, these observations suggest that there are many factors combining to result in the fast location of a specific binding site. The inclusion of these factors into analytically solvable models is difficult and computational models are needed to gain insights. Here Marcovitz and Levy (1xObstacles may facilitate and direct DNA search by proteins. Marcovitz, A. and Levy, Y. Biophys. J. 2013; 104: 2042–2050Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all References1) use simple, structure-based, coarse-grained models and simulations to study the consequences that DNA coverage by obstacles has on the kinetics of one-dimensional searches on DNA. The simulations describe, in a simple way, the role of various effects, including a tuning between hopping and sliding due to the presence of salts, and the role of the mobility of obstacles on the search kinetics.Although all-atom simulations have been a preferred model to simulate biomolecular processes, this is one of many examples where the complexity of the problem does not allow explicit inclusion of all the detailed interrelated effects like hydration, diffusion, and specific binding. Marcovitz and Levy (1xObstacles may facilitate and direct DNA search by proteins. Marcovitz, A. and Levy, Y. Biophys. J. 2013; 104: 2042–2050Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all References1) and previous calculations by Vuzman et al. (9xFacilitated DNA search by multidomain transcription factors: cross talk via a flexible linker. Vuzman, D., Polonsky, M., and Levy, Y. Biophys. J. 2010; 99: 1202–1211Abstract | Full Text | Full Text PDF | PubMed | Scopus (38)See all References9) have shown that coarse-grained simulations capture the effects that many competing interactions have on the search for specific binding sites on DNA by a protein. Previous calculations by Vuzman and co-workers (9xFacilitated DNA search by multidomain transcription factors: cross talk via a flexible linker. Vuzman, D., Polonsky, M., and Levy, Y. Biophys. J. 2010; 99: 1202–1211Abstract | Full Text | Full Text PDF | PubMed | Scopus (38)See all References, 10xDNA search efficiency is modulated by charge composition and distribution in the intrinsically disordered tail. Vuzman, D. and Levy, Y. Proc. Natl. Acad. Sci. USA. 2010; 107: 21004–21009Crossref | PubMed | Scopus (62)See all References) have shown that intrinsically disordered tails in DNA binding proteins help the protein intersegmental transfer by a mechanism in which the protein jumps between distant DNA regions via an intermediate in which the disordered tail and the folded regions of the protein are transiently bound to different DNA segments. Givaty and Levy (11xProtein sliding along DNA: dynamics and structural characterization. Givaty, O. and Levy, Y. J. Mol. Biol. 2009; 385: 1087–1097Crossref | PubMed | Scopus (90)See all References11) also found that the efficiency of the search is significantly enhanced at high salt concentration due to a larger number of hopping events, with optimal searches for occurrences when the protein spends ∼20% sliding along the DNA and ∼80% hopping and performing three-dimensional diffusion, in absence of obstacles. In this issue, Marcovitz and Levy (1xObstacles may facilitate and direct DNA search by proteins. Marcovitz, A. and Levy, Y. Biophys. J. 2013; 104: 2042–2050Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all References1) show that the effect of adding obstacles is not monotonic as a result from the competition between two main effects. That is, at low obstacle occupancy, the search is similar to the case of no obstacles; at very high concentration of obstacles, the protein has no accessibility to the DNA.At moderate occupancies (20%), there is a reduction in the effective one-dimensional diffusion coefficient (mean square deviation/time) relative to the coefficient for naked DNA. Interestingly, at slightly higher occupancies (34%) the one-dimensional diffusion coefficient is recovered. The authors conclude that the increase in obstacle occupancy may interfere with the optimal population of the search mechanism of 80% hopping, 20% sliding. They find that, for moderate occupancies, the one-dimensional search oversamples the linker regions and does not enhance the search, whereas for higher occupancies, the protein performs more hopping events.Although the specific values for the threshold occupancies (20 vs. 34%) and the percentage of hopping (80%) versus sliding (20%) depend on the specific, ad hoc, parameters and the simplicity of the model, the competition between these to effects may be real. Let’s wait and see what the experiments show.