We investigate diffusion-limited reactions between a diffusing particle and a target site on a semiflexible polymer, a key factor determining the kinetics of DNA-protein binding and polymerization of cytoskeletal filaments. Our theory focuses on two competing effects: polymer shape fluctuations, which speed up association, and the hydrodynamic coupling between the diffusing particle and the chain, which slows down association. Polymer bending fluctuations are described using a mean field dynamical theory, while the hydrodynamic coupling between polymer and particle is incorporated through a simple heuristic approximation. Both of these we validate through comparison with Brownian dynamics simulations. Neither of the effects has been fully considered before in the biophysical context, and we show they are necessary to form accurate estimates of reaction processes. The association rate depends on the stiffness of the polymer and the particle size, exhibiting a maximum for intermediate persistence length and a minimum for intermediate particle radius. In the parameter range relevant to DNA-protein binding, the rate increase is up to 100% compared to the Smoluchowski result for simple center-of-mass motion. The quantitative predictions made by the theory can be tested experimentally.
Several recent experiments suggest that sharply bent DNA has a surprisingly high bending flexibility, but the cause of this flexibility is poorly understood. Although excitation of flexible defects can explain these results, whether such excitation can occur with the level of DNA bending in these experiments remains unclear. Intriguingly, the DNA contained preexisting nicks in most of these experiments but whether nicks might play a role in flexibility has never been considered in the interpretation of experimental results. Here, using full-atom molecular dynamics simulations, we show that nic…
The strong bending of polymers is poorly understood. We propose a general quantitative framework of polymer bending that includes both the weak and strong bending regimes on the same footing, based on a single general physical principle. As the bending deformation increases beyond a certain (polymer-specific) point, the change in the convexity properties of the effective bending energy of the polymer makes the harmonic deformation energetically unfavorable: in this strong bending regime the energy of the polymer varies linearly with the average bending angle as the system follows the convex hu…
To characterize the thermodynamical equilibrium of DNA chains interacting with a solution of non-specific binding proteins, a Flory-Huggins free energy model was implemented. We explored the dependence on DNA and protein concentrations of the DNA collapse. For physiologically relevant values of the DNA-protein affinity, this collapse gives rise to a biphasic regime with a dense and a dilute phase; the corresponding phase diagram was computed. Using an approach based on Hamiltonian paths, we show that the dense phase has either a molten globule or a crystalline structure, depending on the DNA b…
Complex DNA topological structures, including polymer loops, are frequently observed in biological processes when protein molecules simultaneously bind to several distant sites on DNA. However, the molecular mechanisms of formation of these systems remain not well understood. Existing theoretical studies focus only on specific interactions between protein and DNA molecules at target sequences. However, the electrostatic origin of primary protein-DNA interactions suggests that interactions of proteins with all DNA segments should be considered. Here we theoretically investigate the role of non-…
The emerging field of hybrid DNA - protein nanotechnology brings with it the potential for many novel materials which combine the addressability of DNA nanotechnology with versatility of protein interactions. However, the design and computational study of these hybrid structures is difficult due to the system sizes involved. To aid in the design and in silico analysis process, we introduce here a coarse-grained DNA/RNA-protein model that extends the oxDNA/oxRNA models of DNA/RNA with a coarse-grained model of proteins based on an anisotropic network model representation. Fully equipped with an…
Experimental data of the DNA cyclization (J-factor) at short length scales, as a way to study the elastic behavior of tightly bent DNA, exceed the theoretical expectation based on the wormlike chain (WLC) model by several orders of magnitude. Here, we propose that asymmetric bending rigidity of the double helix in the groove direction can be responsible for extreme bendability of DNA at short length scales and it also facilitates DNA loop formation at these lengths. To account for the bending asymmetry, we consider the asymmetric elastic rod (AER) model which has been introduced and parametriz…
The bacterial genome is organized in a structure called the nucleoid by a variety of associated proteins. These proteins can form complexes on DNA that play a central role in various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, which forms an essential component of the segregation machinery in many bacteria. ChIP-Seq experiments show that ParB proteins localize around centromere-like parS sites on the DNA to which ParB binds specifically, and spreads from there over large sections of the chromosome. Recent theoretical and experiment…
The Integration Host Factor is a pH-responsive protein that switches from DNA bending to DNA bridging in acidic biofilm-like conditions
School of Physics and Astronomy, University of Edinburgh（爱丁堡大学物理与天文学院）；School of Biological Sciences, University of Edinburgh（爱丁堡大学生物科学学院）；School of Physics, Engineering & technology, University of York（约克大学物理、工程与技术学院）；Department of Biology, University of York（约克大学生物系）
Using analytical approach and Monte-Carlo (MC) simulations, we study the elastic behaviour of the intrinsically twisted elastic ribbons with bending anisotropy, such as double-stranded DNA (dsDNA), in two-dimensional (2D) confinement. We show that, due to the bending anisotropy, the persistence length of dsDNA in 2D conformations is always greater than 3D conformations. This result is in consistence with the measured values for DNA persistence length in 2D and 3D in equal biological conditions. We also show that in 2D, an anisotropic, intrinsically twisted polymer exhibits an implicit twist-be…
The flexibility of short DNA fragments is studied by a Hamiltonian model which treats the inter-strand and intra-strand forces at the level of the base pair. The elastic response of a set of homogeneous helices to externally applied forces is obtained by computing the average bending angles between adjacent base pairs along the molecule axis. The ensemble averages are performed over a room temperature equilibrium distribution of base pair separations and bending fluctuations. The analysis of the end-to-end distances and persistence lengths shows that even short sequences with less than $100$ b…
DNA end tethering through break-induced DNA--protein condensation
Max Planck Institute for the Physics of Complex Systems（马克斯·普朗克复杂系统物理研究所）；Technische Universität Dresden（德累斯顿工业大学）；Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden（德累斯顿工业大学生物技术中心分子与细胞生物工程中心）；Max Planck Institute of Molecular Cell Biology and Genetics（马克斯·普朗克细胞生物学与遗传学研究所）；Center for Systems Biology Dresden（德累斯顿系统生物学中心）；Cluster of Excellence Physics of Life, Technische Universität Dresden（德累斯顿工业大学“生命物理学”卓越集群）
Recent work indicates that twist-bend coupling plays an important role in DNA micromechanics. Here we investigate its effect on bent DNA. We provide an analytical solution of the minimum-energy shape of circular DNA, showing that twist-bend coupling induces sinusoidal twist waves. This solution is in excellent agreement with both coarse-grained simulations of minicircles and nucleosomal DNA data, which is bent and wrapped around histone proteins in a superhelical conformation. Our analysis shows that the observed twist oscillation in nucleosomal DNA, so far attributed to the interaction with t…
We show how coarse-grained modelling combined with umbrella sampling using distance-based order parameters can be applied to compute the free-energy landscapes associated with mechanical deformations of large DNA nanostructures. We illustrate this approach for the strong bending of DNA nanotubes and the potentially bistable landscape of twisted DNA origami sheets. The homogeneous bending of the DNA nanotubes is well described by the worm-like chain model; for more extreme bending the nanotubes reversibly buckle with the bending deformations localized at one or two "kinks". For a twisted one-la…
We propose a dynamical model depicting the interactions between DNA and a specific binding protein involving long range transmissions. The dynamics rely on the coupling between Hydrogen bonds formed between DNA and protein and between the base pairs because they account for site specificity of the binding. We adopt the Morse potential with coupling terms to construct the Hamiltonian. This model gives rise to a breather excitation, corresponding to the DNA bubble formation, which propagates as the carrier of genetic information. We examine the various kind of possible coupling dynamics and sugg…
Coupling between denaturation and chain conformations in DNA: stretching, bending, torsion and finite size effects
我们进一步开发了耦合DNA中的变性和链构象的统计模型（Palmeri J，Manghi M和Destainville N 2007 Phys. Rev. Lett. 99 088103）。我们的离散螺旋蠕虫链模型明确考虑了三个弹性自由度，即聚合物的拉伸，弯曲和扭转。通过整合这些外部变量，构象熵有助于气泡成核（碱基对的打开），这揭示了DNA解链机制。由于单体长度、弯曲模量和扭转模量的值在dsDNA和ssDNA中显著不同，因此这些效应是重要的。此外，我们探讨在这种情况下，一个额外的循环熵的作用和分析有限尺寸的影响，在实验的情况下，polydA-polydT是由两个G-C链，以及自由聚合物夹紧。
Hfq is a bacterial protein that is involved in several aspects of nucleic acids metabolism. It has been described as one of the nucleoid associated proteins shaping the bacterial chromosome, although it is better known to influence translation and turnover of cellular RNAs. Here, we explore the role of Escherichia coli Hfq C-terminal domain in the compaction of double stranded DNA. Various experimental methodologies, including fluorescence microscopy imaging of single DNA molecules confined inside nanofluidic channels, atomic force microscopy, isothermal titration microcalorimetry, and electro…
Advances in DNA nanotechnology have stimulated the search for simple motifs that can be used to control the properties of DNA nanostructures. One such motif, which has been used extensively in structures such as polyhedral cages, two-dimensional arrays, and ribbons, is a bulged duplex, that is two helical segments that connect at a bulge loop. We use a coarse-grained model of DNA to characterize such bulged duplexes. We find that this motif can adopt structures belonging to two main classes: one where the stacking of the helices at the center of the system is preserved, the geometry is roughly…
Many fundamental biological processes are regulated by protein-DNA complexes called {\it synaptosomes}, which possess multiple interaction sites. Despite the critical importance of synaptosomes, the mechanisms of their formation remain not well understood. Because of the multi-site nature of participating proteins, it is widely believed that their search for specific sites on DNA involves the formation and breaking of DNA loops and sliding in the looped configurations. In reality, DNA in live cells is densely covered by other biological molecules that might interfere with the formation of syna…
We study the compression and extension dynamics of a DNA-like polymer interacting with non-DNA binding and DNA-binding proteins, by means of computer simulations. The geometry we consider is inspired by recent experiments probing the compressional elasticity of the bacterial nucleoid (DNA plus associated proteins), where DNA is confined into a cylindrical container and subjected to the action of a "piston" - a spherical bead to which an external force is applied. We quantify the effect of steric interactions (excluded volume) on the force-extension curves as the polymer is compressed. We find …
The zinc finger structure where a Zn2+ ion binds to 4 cysteine or histidine amino acids in a tetrahedral structure is very common motif of nucleic acid binding proteins. The corresponding interaction model is present in 3% of the genes of human genome. As a result, zinc finger has been shown to be extremely useful in various therapeutic and research capacities, as well as in biotechnology. In stable configuration, the cysteine amino acids are deprotonated and become negatively charged. This means the Zn2+ ion is overscreened by 4 cysteine charges (overcharged). It is question of whether this o…
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 i…
