The Hill coefficient is often used as a direct measure of the cooperativity of binding processes. It is an essential tool for probing properties of reactions in many biochemical systems. Here we analyze existing experimental data and demonstrate that
the Hill coefficient characterizing the binding of transcription factors to their cognate sites can in fact be larger than one -- the standard indication of cooperativity -- even in the absence of any standard cooperative binding mechanism. By studying the problem analytically, we demonstrate that this effect occurs due to the disordered binding energy of the transcription factor to the DNA molecule and the steric interactions between the different copies of the transcription factor. We show that the enhanced Hill coefficient implies a significant reduction in the number of copies of the transcription factors which is needed to occupy a cognate site and, in many cases, can explain existing estimates for numbers of the transcription factors in cells. The mechanism is general and should be applicable to other biological recognition processes.
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.
We consider a large class of two-lane driven diffusive systems in contact with reservoirs at their boundaries and develop a stability analysis as a method to derive the phase diagrams of such systems. We illustrate the method by deriving phase diagra
ms for the asymmetric exclusion process coupled to various second lanes: a diffusive lane; an asymmetric exclusion process with advection in the same direction as the first lane, and an asymmetric exclusion process with advection in the opposite direction. The competing currents on the two lanes naturally lead to a very rich phenomenology and we find a variety of phase diagrams. It is shown that the stability analysis is equivalent to an `extremal current principle for the total current in the two lanes. We also point to classes of models where both the stability analysis and the extremal current principle fail.
The extraction of membrane tubes by molecular motors is known to play an important role for the transport properties of eukaryotic cells. By studying a generic class of models for the tube extraction, we discover a rich phase diagram. In particular w
e show that the density of motors along the tube can exhibit shocks, inverse shocks and plateaux, depending on parameters which could in principle be probed experimentally. In addition the phase diagram exhibits interesting reentrant behavior.
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.
