Problems of search and recognition appear over different scales in biological systems. In this review we focus on the challenges posed by interactions between proteins, in particular transcription factors, and DNA and possible mechanisms which allow
for a fast and selective target location. Initially we argue that DNA-binding proteins can be classified, broadly, into three distinct classes which we illustrate using experimental data. Each class calls for a different search process and we discuss the possible application of different search mechanisms proposed over the years to each class. The main thrust of this review is a new mechanism which is based on barrier discrimination. We introduce the model and analyze in detail its consequences. It is shown that this mechanism applies to all classes of transcription factors and can lead to a fast and specific search. Moreover, it is shown that the mechanism has interesting transient features which allow for stability at the target despite rapid binding and unbinding of the transcription factor from the target.
This review examines intermittent target search strategies, which combine phases of slow motion, allowing the searcher to detect the target, and phases of fast motion during which targets cannot be detected. We first show that intermittent search str
ategies are actually widely observed at various scales. At the macroscopic scale, this is for example the case of animals looking for food ; at the microscopic scale, intermittent transport patterns are involved in reaction pathway of DNA binding proteins as well as in intracellular transport. Second, we introduce generic stochastic models, which show that intermittent strategies are efficient strategies, which enable to minimize the search time. This suggests that the intrinsic efficiency of intermittent search strategies could justify their frequent observation in nature. Last, beyond these modeling aspects, we propose that intermittent strategies could be used also in a broader context to design and accelerate search processes.
We present a generic model of cell motility generated by acto-myosin contraction of the cell cortex. We identify analytically dynamical instabilities of the cortex and show that they trigger spontaneous cortical flows which in turn can induce cell mi
gration in 3-dimensional (3D) environments as well as bleb formation. This contractility--based mechanism, widely independent of actin treadmilling, appears as an alternative to the classical picture of lamellipodial motility on flat substrates. Theoretical predictions are compared to experimental data of tumor cells migrating in 3D matrigel and suggest that this mechanism could be a general mode of cell migration in 3D environments.
We present a theoretical model of facilitated diffusion of proteins in the cell nucleus. This model, which takes into account the successive binding/unbinding events of proteins to DNA, relies on a fractal description of the chromatin which has been
recently evidenced experimentally. Facilitated diffusion is shown quantitatively to be favorable for a fast localization of a target locus by a transcription factor, and even to enable the minimization of the search time by tuning the affinity of the transcription factor with DNA. This study shows the robustness of the facilitated diffusion mechanism, invoked so far only for linear conformations of DNA.
Search problems at various scales involve a searcher, be it a molecule before reaction or a foraging animal, which performs an intermittent motion. Here we analyze a generic model based on such type of intermittent motion, in which the searcher alter
nates phases of slow motion allowing detection, and phases of fast motion without detection. We present full and systematic results for different modeling hypotheses of the detection mechanism in space dimension 1, 2 and 3. Our study completes and extends the results of our recent letter [Loverdo {it et al.} Nature Physics {bf 4}, 134 (2008)] and gives the necessary calculation details. In addition, a new modeling of the detection phase is presented. We show that the mean target detection time can be minimized as a function of the mean duration of each phase in dimension 1, 2 and 3. Importantly, this optimal strategy does not depend on the details of the modeling of the slow detection phase, which shows the robustness of our results. We believe that this systematic analysis can be used as a basis to study quantitatively various real search problems involving intermittent behaviors.
We present a general framework, applicable to a broad class of random walks on complex networks, which provides a rigorous lower bound for the mean first-passage time of a random walker to a target site averaged over its starting position, the so-cal
led global mean first-passage time (GMFPT). This bound is simply expressed in terms of the equilibrium distribution at the target, and implies a minimal scaling of the GMFPT with the network size. We show that this minimal scaling, which can be arbitrarily slow for a proper choice of highly connected target, is realized under the simple condition that the random walk is transient at the target site, and independently of the small-world, scale free or fractal properties of the network. Last, we put forward that the GMFPT to a specific target is not a representative property of the network, since the target averaged GMFPT satisfies much more restrictive bounds, which forbid any sublinear scaling with the network size.
Genomic expression depends critically both on the ability of regulatory proteins to locate specific target sites on a DNA within seconds and on the formation of long lived (many minutes) complexes between these proteins and the DNA. Equilibrium exper
iments show that indeed regulatory proteins bind tightly to their target site. However, they also find strong binding to other non-specific sites which act as traps that can dramatically increase the time needed to locate the target. This gives rise to a conflict between the speed and stability requirements. Here we suggest a simple mechanism which can resolve this long-standing paradox by allowing the target sites to be located by proteins within short time scales even in the presence of traps. Our theoretical analysis shows that the mechanism is robust in the presence of generic disorder in the DNA sequence and does not require a specially designed target site.
The cell cytoskeleton is a striking example of active medium driven out-of-equilibrium by ATP hydrolysis. Such activity has been shown recently to have a spectacular impact on the mechanical and rheological properties of the cellular medium, as well
as on its transport properties : a generic tracer particle freely diffuses as in a standard equilibrium medium, but also intermittently binds with random interaction times to motor proteins, which perform active ballistic excursions along cytoskeletal filaments. Here, we propose for the first time an analytical model of transport limited reactions in active media, and show quantitatively how active transport can enhance reactivity for large enough tracers like vesicles. We derive analytically the average interaction time with motor proteins which optimizes the reaction rate, and reveal remarkable universal features of the optimal configuration. We discuss why active transport may be beneficial in various biological examples: cell cytoskeleton, membranes and lamellipodia, and tubular structures like axons.
The time needed for a particle to exit a confining domain through a small window, called the narrow escape time (NET), is a limiting factor of various processes, such as some biochemical reactions in cells. Obtaining an estimate of the mean NET for a
given geometric environment is therefore a requisite step to quantify the reaction rate constant of such processes, which has raised a growing interest in the last few years. In this Letter, we determine explicitly the scaling dependence of the mean NET on both the volume of the confining domain and the starting point to aperture distance. We show that this analytical approach is applicable to a very wide range of stochastic processes, including anomalous diffusion or diffusion in the presence of an external force field, which cover situations of biological relevance.
