Biophysical journal最新文献

There has been an increasing demand for longer-timescale molecular dynamics (MD) simulations of larger biomolecular systems. To meet these demands, using the C++ API of OpenMM, we developed a fast and flexible MD software, OpenCafeMol, for residue-resolution protein and lipid models that shows high performance on graphics processing unit (GPU) machines. We validated OpenCafeMol for folding small proteins, lipid membrane dynamics, and membrane protein structures. Benchmark tests of the computation times showed that OpenCafeMol with one GPU for proteins and lipid membranes is approximately 100 and 240 times faster than the corresponding simulations on a typical CPU machine (eight cores), respectively. Taking advantage of the high speed of OpenCafeMol, we applied it to two sets of vesicle fusion simulations; one driven by force and the other coupled with conformational dynamics of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. In the latter MD simulation at a high temperature resulted in vesicle docking and pore formation, followed by fusion, which are coupled with local folding of linkers in the SNARE complex. This opens up a new avenue to study membrane-fusion mechanisms via MD simulations. The source code for OpenCafeMol is fully available.

F_o domain of ATP synthase functions as a rotary molecular motor, coupling proton translocation with the rotation of the c-ring rotor. This process involves proton uptake at the entry half-channel, rotor rotation, and proton release to the exit half-channel. Although the overall coupling mechanism is established, the design principle for efficient rotation remains unclear. Here, we employed hybrid molecular simulations-combining coarse-grained modeling and Monte Carlo methods-to investigate the roles of side-chain flexibility at proton-binding residues and the angular mismatch between the proton uptake process and the proton release process. Our results indicate that both factors promote rotational activity, with side-chain flexibility playing a more significant role. Comparable analysis of F_o structures from different species revealed that the key residue geometry is conserved, and that the asymmetric geometry of the two half-channels aligns with the mechanism suggested by simulation. These findings highlight a conserved design principle that enhances rotational efficiency and offers a mechanistic basis for engineering synthetic rotary systems.

The ATP molecule serves as an energy currency in eukaryotes (and all life), providing the energy needed for many essential cellular processes. But the extent to which substantial spatial differences exist in ATP concentration in the cell remains incompletely known. It is variously argued that ATP diffuses too quickly for large gradients to be established, or that the high rates of ATP production and use (sources and sinks) can support large gradients even with rapid diffusion-and microscopic models and detailed experiments in different specific cases support both pictures. Here, we attempt a mesoscopic investigation, using reaction-diffusion modeling in a simple biophysical picture of the cell to attempt to ask, generally, which conditions cause substantial ATP gradients to emerge within eukaryotic cells. If ATP sources (like mitochondria) or sinks (like the nucleus) are spatially clustered, large fold changes in concentration can exist across the cell; if sources and sinks are more spread, then rapid diffusion indeed prevents large gradients from being established. This dependence holds in model cells of different sizes, suggesting its generality across cell types. Our theoretical work will complement developing intracellular approaches exploring ATP concentration inside eukaryotic cells.

The structural organization of chromatin is intricately influenced by the length of linker DNA connecting nucleosomes. Some studies have suggested preferred linker lengths of 10n and 10n+5 base pairs (bp) (n = integer). Because these lengths dictate the rotational orientation of successive nucleosomes in the fiber axis, they can markedly affect chromatin fiber compaction and topology. Using a refined mesoscale chromatin model with 5-bp resolution, we investigate the influence of linker DNA periodicity, linker histone density, salt concentration, and starting fiber topology on chromatin architecture for regular fibers versus "life-like" fibers, the latter with irregular spacing between nucleosomes. Our results reveal that regular fibers with 10n linkers exhibit compact zigzag configurations, whereas 10n+5 linkers generate more open and flexible structures. However, these effects are pronounced only for short linker lengths, as longer linkers are more heterogeneous. Moreover, increased linker histone density further enhances compaction for long linker lengths, and lower salt concentration modifies chromatin topologies, diminishing periodicity-driven effects. In addition, any periodicity effect in tightly packed solenoid configurations is much less pronounced. All these trends for regular fibers are reduced in life-like fibers with irregularly spaced nucleosomes, despite having the same average spacing. Moreover, the trend details depend highly on specific features of the fiber architecture as designed in experiments and simulations. Overall, our study highlights how reported differences depend on modeling details and emphasizes the role of linker DNA length in regulating chromatin fiber architecture and its potential implications for genome accessibility and expression.

Protein phosphorylation is a common and essential post-translational modification that affects biochemical properties and regulates biological activities. Phosphorylation is particularly common for intrinsically disordered proteins and can significantly modulate their function and potential to interact with binding partners. To understand the biophysical origins of how phosphorylation of disordered proteins influences their function, it is valuable to investigate how the modifications lead to changes in their conformational ensembles. Here, we have used a top-down data-driven approach to develop a coarse-grained molecular dynamics model compatible with the CALVADOS protein simulation model to study the effects of serine and threonine phosphorylation on the global structural properties of disordered proteins. We parameterize the model using experimental data on the effects of phosphorylation on global dimensions. By comparing with baseline models and simulations using the phosphomimetics aspartate and glutamate, we show that the effect of phosphorylation on the global dimensions of disordered proteins is mostly driven by the additional charge. We envisage that our model can be applied to study the effects of phosphorylation of disordered proteins at the proteome scale as well as to study the important roles of protein phosphorylation on phase separation.