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Register a new userEphemeral protein binding to DNA shapes stable nuclear bodies and chromatin domains
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Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool whilst the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins; these proteins switch between two states -- active (binding) and inactive (non-binding). This system provides a model for any DNA-binding protein that can be modified post-translationally to change its affinity for DNA (e.g., like the phosphorylation of a transcription factor). Due to this out-of-equilibrium process, proteins spontaneously assemble into clusters of self-limiting size, as individual proteins in a cluster exchange with the soluble pool with kinetics like those seen in photo-bleaching experiments. This behavior contrasts sharply with that exhibited by equilibrium, or non-switching, proteins that exist only in the binding state; when these bind to DNA non-specifically, they form clusters that grow indefinitely in size. Our results point to post-translational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, non-equilibrium, protein clusters with the properties of nuclear bodies. Such active modification also reshapes intra-chromatin contacts to give networks resembling those seen in topologically-associating domains, as switching markedly favors local (short-range) contacts over distant ones.
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Proteins form a very important class of polymers. In spite of major advances in the understanding of polymer science, the protein problem has remained largely unsolved. Here, we show that a polymer chain viewed as a tube not only captures the well-known characteristics of polymers and their phases but also provides a natural explanation for many of the key features of protein behavior. There are two natural length scales associated with a tube subject to compaction -- the thickness of the tube and the range of the attractive interactions. For short tubes, when these length scales become comparable, one obtains marginally compact structures, which are relatively few in number compared to those in the generic compact phase of polymers. The motifs associated with the structures in this new phase include helices, hairpins and sheets. We suggest that Nature has selected this phase for the structures of proteins because of its many advantages including the few candidate strucures, the ability to squeeze the water out from the hydrophobic core and the flexibility and versatility associated with being marginally compact. Our results provide a framework for understanding the common features of all proteins.
We consider the dynamics of a rigid filament in a motor protein assay under external loading. The motor proteins are modeled as active harmonic linkers with tail ends immobilized on a substrate. Their heads attach to the filament stochastically to extend along it, resulting in a force on the filament, before detaching. The rate of extension and detachment are load dependent. Here we formulate and characterize the governing dynamics in the mean field approximation using linear stability analysis, and direct numerical simulations of the motor proteins and filament. Under constant loading, the system shows transition from a stable configuration to instability towards detachment of the filament from motor proteins. Under elastic loading, we find emergence of stable limit cycle oscillations via a supercritical Hopf bifurcation with change in activity and the number of motor proteins. Numerical simulations of the system for large number of motor proteins show good agreement with the mean field predictions.
The DNA molecule, apart from carrying the genetic information, plays a crucial role in a variety of biological processes and find applications in drug design, nanotechnology and nanoelectronics. The molecule undergoes significant structural transitions under the influence of forces due to physiological and non-physiological environments. Here, we summarize the insights gained from simulations and single-molecule experiments on the structural transitions and mechanics of DNA under force, as well as its elastic properties, in various environmental conditions, and discuss appealing future directions.
In gene expression, various kinds of proteins need to bind to specific locus of DNA. It is still not clear how these proteins find their target locus. In this study, the mean first-passage time (FPT) of protein binding to its target locus on DNA chain is discussed by a chain-space coupled model. Our results show that the 1-dimensional diffusion constant has a critical value, with which the mean time spent by a protein to find its target locus is almost independent of the binding rate of protein to DNA chain and the detachment rate from DNA chain. Which implies that, the frequency of protein binding to DNA and the sliding time on DNA chain have little influence on the search efficiency, and therefore whether or not the 1-dimensional sliding on DNA chain increases the search efficiency depends on the 1-dimensional diffusion constant of the protein on DNA chain. This study also finds that only protein bindings to DNA loci which are close to the target locus help to increase the search efficiency, while bindings to those loci which are far from the target locus might delay the target binding process. As expected, the mean FPT increases with the distance between the initial position of protein in cell space and its target locus on DNA chain. The direct binding probability, which can be regarded as one index to describe if the 1-dimensional sliding along DNA chain is helpful to increase the search efficiency is calculated. Our results show that the influence of 1-dimensional sliding along DNA chain on the search process depends on both diffusion constants of protein in cell space and on the 1-dimensional DNA chain.
By combining analytical results and simulations of various coarse-grained models we investigate the minimal energy shape of DNA minicircles which are torsionally constrained by an imposed over or undertwist. We show that twist-bend coupling, a cross interaction term discussed in the recent DNA literature, induces minimal energy shapes with a periodic alternance of parts with high and low curvature resembling rounded polygons. We briefly discuss the possible experimental relevance of these findings. We finally show that the twist and bending energies of minicircles are governed by renormalized stiffness constants, not the bare ones. This has important consequences for the analysis of experiments involving circular DNA meant to determine DNA elastic constants.
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