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.In all living organisms, from bacteria to man, DNA and chromatin are invariably associated with binding proteins, which organize their structure [1][2][3]. Many of these architectural proteins are molecular bridges that can bind at two or more distinct DNA sites to form loops. For example, bacterial DNA is looped and compacted by the histone-like protein H-NS which has two distinct DNA-binding domains [4]. In eukaryotes, complexes of transcription factors and RNA polymerases stabilize enhancer-promoter loops [5,6,6, 7], while HP1 [9], histone H1 [10], and the polycomb-repressor complex PRC1/2 [5, 11] organize inactive chromatin. Proteins also bind to specific DNA sequences to form larger structures, like nucleoli and the histone-locus, Cajal, and promyeloleukemia bodies [13][14][15][16][17][18]. The selective binding of molecular bridges to active and inactive regions of chromatin has also been highlighted as one possible mechanism underlying the formation of topologically associated domains (TADs) -regions rich in local DNA interactions [6,6,19].From a biophysical perspective, a system made up of DNA and DNA-binding proteins exhibits many kinds of interesting and seemingly counter-intuitive behaviour, such as the clustering of proteins in the absence of any attractive interaction between them. This process is driven by the "bridging-induced attraction" [20]. In conjunction with the specific patterning of binding sites found on a whole human chromoso...

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) DNAbinding proteins; these proteins switch between two states -active (binding) and inactive (nonbinding). This system provides a model for any DNA-binding protein that can be modified posttranslationally 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.

Conspectus First-principles molecular dynamics (FPMD) and its quantum mechanical-molecular mechanical (QM/MM) extensions are powerful tools to follow the real-time dynamics of a broad variety of systems in their ground as well as electronically excited states. The continued advances in computational power have enabled simulations of QM regions of larger sizes for more extended time scales. In addition, development of the parallel algorithms has boosted the performance of QM/MM methods even on existing computer architectures. In the case of density functional-based FPMD, systems of several hundreds to thousands of atoms can now be customarily simulated for tens to hundreds of picoseconds. In spite of this progress, the time scale limitations remain severe, especially when high-rung exchange-correlation functionals or high-level wave function based quantum mechanical methods are used. To ameliorate this, a large number of enhanced sampling methods have been introduced but most of the approaches that have been developed to increase the efficiency of FPMD based simulations sacrifice the real-time dynamics in favor of enhancing sampling. Here, we present some recent advances in boosting the efficiency of FPMD based simulations while keeping the full dynamic information. These include a highly efficient recent implementation of FPMD-based QM/MM simulations that not only enables fully flexible combinations of different electronic structure methods and force fields via a highly efficient communication library, it also fully exploits parallelism for both quantum and classical descriptions. The second type of acceleration methods we discuss is a large family of specially devised multiple-time-step algorithms that make use of suitable breakups of the total nuclear forces into fast components that can be calculated via lower level methods and slowly varying correction forces evaluated with a high-level method at long time intervals. The computational gain of this scheme mostly depends on the cost difference between the two methods and advantageous combinations can yield large speedups without compromising the accuracy of the high-level method. And finally, the third class of FPMD acceleration methods presented here are machine learning models to accelerated FPMD and their powerful combinations with multiple-time-step techniques. The combination of all the approaches enables substantial speedups of FPMD simulations of several orders of magnitude while fully preserving the real-time dynamics and accuracy.

Schistosomiasis is ad iseaseo fp overty affecting millionso fp eople. Praziquantel (PZQ),w ith its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derivedfrom oxamniquine (OXA), an old antischistosomald rug:f errocene-containing (Fc-CH 2-OXA),r uthenocene-containing (Rc-CH 2-OXA) and benzene-containing (Ph-CH 2-OXA) OXA derivatives. These derivatives showed excellent in vitro activity againstb oth Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducteda dditional in-depthp reclinical studiesa nd report in this investigation on metabolic stability studies, in vivos tudies on S. haematobium and juvenile S. mansoni,c omputational simulations,a nd formulation development. Molecular dynamicss imulations supportedt he in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reasonw hy the promising in vitro activity did not translate into in vivo activityo nS. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as aw ay to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability,t or each an active concentration in the microenvironment of the parasite.

We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being "colored" according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi-and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is "fitting-free" in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can -in principle -be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.