The growing interest in the complexity of biological interactions is continuously driving the need to increase system size in biophysical simulations, requiring not only powerful and advanced hardware but adaptable software that can accommodate a large number of atoms interacting through complex forcefields. To address this, we developed and implemented strategies in the GENESIS molecular dynamics package designed for large numbers of processors. Long-range electrostatic interactions were parallelized by minimizing the number of processes involved in communication. A novel algorithm was implemented for nonbonded interactions to increase single instruction multiple data (SIMD) performance, reducing memory usage for ultra large systems.Memory usage for neighbor searches in real-space nonbonded interactions was reduced by approximately 80%, leading to significant speedup. Using experimental data describing physical 3D chromatin interactions, we constructed the first atomistic model of an entire gene locus (GATA4). Taken together, these developments enabled the first billion-atom simulation of an intact biomolecular complex, achieving scaling to 65,000 processes (130,000 processor cores) with

We approach the problem of coil−globule transition dynamics numerically by Brownian dynamics simulations. This method allows us to study the behavior of polymer chains of varying stiffness and the effects of bending stiffness on chain morphology during the process of coil− globule collapse, imitating globule formation in poor solvent conditions. We record and analyze a three-stage process of globule formation for flexible chains: (1) nucleation, (2) coalescence of nuclei, and (3) collapsed globule formation. Stiffer chains undergo similar formation stages; however, the "raindrops" formed by these chains are elongated (unlike spherical structures formed by flexible chains) and exhibit regular packing of chains into antiparallel hairpin structures. In order to assess the transition dynamics quantitatively, polymer chain configurations were analyzed by generating contact maps and contact frequency histograms for all given configurations. These clusters are initial-configuration-dependent, and their growth and intercluster contacts have direct analogy with the process of raindrop coalescence.

We study the dynamics of polymer chain collapse into a globular state in poor solvent, as a function of chain flexibility. We examine the compactness of the folded globule assessing the direct contact and a larger length-scale structural characteristics at various persistence lengths l p. We discover that semiflexible polymer chains with a specific stiffness (l p ≈ 8 monomers) form the most densely folded structures, independently of the chain length, a phenomenon due to nematic-like hairpin formation and stacking of hairpin segments in the most compact state. Even in this most compactly folded state, the number of contacts between monomers (accounting for covalent bonds as well as noncovalent physical interactions) is still low, and the globule is only just above the marginal stability threshold. We identify morphological changes associated with the dynamics of semiflexible chain collapse: flexible chains fold into globules, less flexible form rod-like structures, followed by toroidal structures of different geni, and finally, even stiffer chains form highly elongated rods. We also study the time of collapse as a function of persistence length, which shows that stiff chains take much longer to reach their elongated lowest energy state. We propose that polymer chain stiffness, as a regulator of both local and global chain compactness, is highly important in biological systems and in the dynamics of DNA and protein folding.

We re-examine the physical origin of the polymer glass transition from the point of view of marginal rigidity, which is achieved at a certain average number of mechanically active intermolecular contacts per monomer. In the case of polymer chains in a melt/poor solvent, each monomer has two neighbors bound by covalent bonds and also a number of central-force contacts modelled by the Lennard-Jones (LJ) potential. We find that when the average number of contacts per monomer (covalent and non-covalent) exceeds the critical value z* ≈ 4, the system becomes solid and the dynamics arrested - a state that we declare the glass. Coarse-grained Brownian dynamics simulations show that at sufficient strength of LJ attraction (which effectively represents the depth of quenching, or the quality of solvent) the polymer globule indeed crosses the threshold of z*, and becomes a glass with a finite zero-frequency shear modulus, G∝ (z-z*). We verify this by showing the distinction between the 'liquid' polymer droplet at z < z*, which changes shape and adopts the spherical conformation in equilibrium, and the glassy 'solid' droplet at z > z*, which retains its shape frozen at the moment of z* crossover. These results provide a robust microscopic criterion to tell the liquid apart from the glass for the linear polymers.

The problem of transport through nanochannels is one of the major questions in cell biology, with a wide range of applications. In this paper we discuss the process of spontaneous translocation of molecules (Brownian particles) by ratcheted diffusion: a problem relevant for protein translocation along bacterial flagella or injectosome complex, or DNA translocation by bacteriophages. We use molecular dynamics simulations and statistical theory to identify two regimes of transport: at low rate of particle injection into the channel the process is controlled by the individual diffusion towards the open end (the first passage problem), while at a higher rate of injection the crowded regime sets in. In this regime the particle density in the channel reaches a constant saturation level and the resistance force increases substantially, due to the osmotic pressure build-up. To achieve a steady-state transport, the apparatus that injects new particles into a crowded channel has to operate with an increasing power consumption, proportional to the length of the channel and the required rate of transport. The analysis of resistance force, and accordingly -the power required to inject the particles into a crowded channel to overcome its clogging, is also relevant for many microfluidics applications.

Chromosomes are segmented into domains and compartments, but how these structures are spatially related in three dimensions (3D) is unclear. Here, we developed tools that directly extract 3D information from Hi-C experiments and integrate the data across time. With our “4DHiC” method, we use X chromosome inactivation (XCI) as a model to examine the time evolution of 3D chromosome architecture during large-scale changes in gene expression. Our modeling resulted in several insights. Both A/B and S1/S2 compartments divide the X chromosome into hemisphere-like structures suggestive of a spatial phase-separation. During the XCI, the X chromosome transits through A/B, S1/S2, and megadomain structures by undergoing only partial mixing to assume new structures. Interestingly, when an active X chromosome (Xa) is reorganized into an inactive X chromosome (Xi), original underlying compartment structures are not fully eliminated within the Xi superstructure. Our study affirms slow mixing dynamics in the inner chromosome core and faster dynamics near the surface where escapees reside. Once established, the Xa and Xi resemble glassy polymers where mixing no longer occurs. Finally, Xist RNA molecules initially reside within the A compartment but transition to the interface between the A and B hemispheres and then spread between hemispheres via both surface and core to establish the Xi.

The glass transition is one of the few unsolved problems in condensed matter physics: agreement on the cause of the slowing down of structural relaxation in glass-forming liquids is lacking. Glasses are amorphous solids, which do not possess the long-range crystalline order, yet display arrested dynamics and the shear elastic modulus characteristic of equilibrium elasticity. It has been suggested that due to the influence of intramolecular interactions and chain connectivity, the nature of the glass transition in polymers and in standard glass-formers is fundamentally different. Here, we discuss the role of connectivity in polymer glasses, demonstrating that although covalent bonding promotes glass formation, bonding sequentiality that defines a polymer chain is not critical in the bulk: glassy dynamics is purely a result of the number of connections per particle, independently of how these connections are formed, agreeing with the classical Phillips-Thorpe topological constraint theory. We show that bonding sequentiality does play an important role in the surface effects of the glass, highlighting a major difference between polymeric and colloidal glasses. Further, we identify the heterogenous dynamics of model coarse-grained polymer chains both in ‘bulk’ and near the free surface, and demonstrate characteristic domain patterns in local displacement and connectivity.

Background Nuclear processes such as transcription and RNA maturation can be impacted by subnuclear compartmentalization in condensates and nuclear bodies. Here, we characterize the nature of nuclear granules formed by REST corepressor 2 (RCOR2), a nuclear protein essential for pluripotency maintenance and central nervous system development. Results Using biochemical approaches and high-resolution microscopy, we reveal that RCOR2 is localized in nuclear speckles across multiple cell types, including neurons in the brain. RCOR2 forms complexes with nuclear speckle components such as SON, SRSF7, and SRRM2. When cells are exposed to chemical stress, RCOR2 behaves as a core component of the nuclear speckle and is stabilized by RNA. In turn, nuclear speckle morphology appears to depend on RCOR2. Specifically, RCOR2 knockdown results larger nuclear speckles, whereas overexpressing RCOR2 leads to smaller and rounder nuclear speckles. Conclusion Our study suggests that RCOR2 is a regulatory component of the nuclear speckle bodies, setting this co-repressor protein as a factor that controls nuclear speckles behavior.