In this paper, a new method to efficiently simulate diffusion controlled second order chemical reactions is derived and applied to site-specific DNA-binding proteins. The protein enters a spherical cell and propagates via two competing modes, a free diffusion and a DNA-sliding mode, to search for its specific binding site in the center of the cell. There is no need for a straightforward simulation of this process. Instead, an alternative and exact approach is shown to be essentially faster than explicit random-walk simulations. The speed-up of this novel simulation technique is rapidly growing with system size.
Transcription factors are able to associate to their binding sites on DNA faster than the physical limit posed by diffusion. Such high association rates can be achieved by alternating between three-dimensional diffusion and one-dimensional sliding along the DNA chain, a mechanism dubbed Facilitated Diffusion. By studying a collection of transcription factor binding sites of Escherichia coli from the RegulonDB database and of Bacillus subtilis from DBTBS, we reveal a funnel in the binding energy landscape around the target sequences. We show that such a funnel is linked to the presence of gradi…
How type 2 Topoisomerase (TopoII) proteins relax and simplify the topology of DNA molecules is one of the most intriguing open questions in biophysics. Most of the existing models neglect the dynamics of TopoII which is characteristics for proteins searching their targets via facilitated diffusion. Here, we show that dynamic binding of TopoII speeds up the topological relaxation of knotted substrates by enhancing the search of the knotted arc. Intriguingly, this in turn implies that the timescale of topological relaxation is virtually independent of the substrate length. We then discover that …
Unraveling the Allosteric Mechanism and Mechanical Stability of Partial and Complete Loss-of-Function Mutations in p53 DNA-Binding Domain
School of Physics and Astronomy, Beijing Normal University（北京师范大学物理与天文学院）；Faculty of Arts and Sciences, Beijing Normal University at Zhuhai（北京师范大学珠海校区文理学院）
The radiation-induced damages in bio-molecules are ubiquitous processes in radiotherapy, radio-biology and critical to space-projects. In this study we present a precise quantification of the fragmentation mechanisms of deoxyribonucleic acid (DNA) and the molecules surrounding DNA such as oxygen and water under non-equilibrium conditions using the first-principle calculations based on density functional theory (DFT). Our results reveal the structural stability of DNA-bases and backbone that withstand up to a combined threshold of charge and hydrogen abstraction owing to simultaneous direct and…
Protein complexes involved in DNA mismatch repair appear to diffuse along dsDNA in order to locate a hemimethylated incision site via a dissociative mechanism. Here, we study the probability that these complexes locate a given target site via a semi-analytic, Monte Carlo calculation that tracks the association and dissociation of the complexes. We compare such probabilities to those obtained using a non-dissociative diffusive scan, and determine that for experimentally observed diffusion constants, search distances, and search durations $\textit{in vitro}$, there is neither a significant advan…
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）
Complementary DNA strands in solution reliably hybridize to form stable duplexes. We study the kinetics of the hybridization process and the mechanisms by which two initially isolated strands come together to form a stable double helix. We adopt a multi-step computational approach. First, we perform a large number of Brownian dynamics simulations of the hybridization process using the coarse-grained oxDNA2 model. Second, we use these simulations to construct a Markov State Model of DNA dynamics that uses a state decomposition based on the inter-strand hydrogen bonding pattern. Third, we take a…
Molecular dynamics simulations are often used to provide feedback in the design workflow of DNA nanostructures. However, even with coarse-grained models, convergence of distributions from unbiased simulation is slow, limiting applications to equilibrium structural properties. Given the increasing interest in dynamic, reconfigurable, and deformable devices, methods that enable efficient quantification of large ranges of motion, conformational transitions, and mechanical deformation are critically needed. Metadynamics is an automated biasing technique that enables the rapid acquisition of molecu…
The spatiotemporal organization of bacterial cells is crucial for the active segregation of replicating chromosomes. In several species, including Caulobacter crescentus, the ATPase ParA binds to DNA and forms a gradient along the long cell axis. The ParB partitioning complex on the newly replicated chromosome translocates up this ParA gradient, thereby contributing to chromosome segregation. A DNA-relay mechanism - deriving from the elasticity of the fluctuating chromosome - has been proposed as the driving force for this cargo translocation, but a mechanistic theoretical description remains …
This work investigates the interactions of H-NS proteins and bacterial genomic DNA through computer simulations performed with a coarse-grained model. The model was developed specifically to study the switch of H-NS proteins from the DNA-stiffening to the DNA-bridging mode, which has been observed repeatedly upon addition of multivalent cations to the buffer, but is still not understood. Unravelling the corresponding mechanism is all the more crucial, as the regulation properties of H-NS proteins, as well as other nucleoid proteins, are linked to their DNA-binding properties. The simulations r…
