Biophysical journal最新文献

Post-translational modifications (PTM) (including, but not limited to, acetylation, methylation, ubiquitylation, SUMOylation and phosphorylation) offer one of the key regulatory mechanisms available to the cell. Histone PTMs catalyzed by histone modifying enzymes are perhaps the most studied PTMs in the last two decades and are known to play a critical role in regulation of gene expression. There is extensive crosstalk among different PTMs that affects activity and specificity of histone modifying enzymes, but deciphering mechanism and process by which PTMs are written and modified has proved to be challenging without understanding key underlying principles. Therefore, exploration of how PTMs are written under influence of existing PTMs (e.g., on histone) as well as general mechanisms governing their crosstalk are of fundamental importance. In this review article, we examine and analyze some previous results which show that pre-installed PTMs on substrates (e.g., modified peptides or nucleosomes) can stimulate the activity and change the specificity of histone modifying enzymes for installing new PTMs. We term such stimulation effects as PTM-induced substrate-assisted stimulations (PTM-induced SAS) and discuss some possible origin of such stimulations in certain cases. Possible role of water molecules in PTM crosstalk in the nucleosome context is also discussed. Although the focus of this review article is mainly on some of the crosstalk involving histone methylation stimulated by pre-installed methylation, acetylation or ubiquitylation, the PTM-induced SAS also exists in some other PTM crosstalk, and PTM-induced inhibition can be present as well. PTM-induced stimulations or inhibitions of enzyme activity may provide a unique way and attractive mechanism for regulation and signaling, but detailed studies are still necessary to fully understand how the stimulations/inhibitions are created and translated into altered activities and specificity for histone modifying enzymes or some other systems.

Plasma membranes (PMs) exhibit asymmetry between their two leaflets in terms of phospholipid headgroups, unsaturation, and resulting membrane properties, such as packing and fluidity. Lateral heterogeneity, including the formation of lipid domains, is another crucial aspect of PMs with significant biological implications. However, the nature and even the existence of lipid domains in the two leaflets of PMs remain elusive, hindering a complete understanding of the significance of lipid asymmetry. Using coarse-grained molecular dynamics simulations of the asymmetric PM, we find that the outer leaflet lipids are highly ordered and largely uniformly distributed, whereas the inner leaflet separates into nanoscale (≈10 nm) highly ordered and more disordered domains, exhibiting highly dynamic domain fusion and fission events. This structural asymmetry is further reinforced by asymmetric lateral stress resulting from a cholesterol bias toward the outer leaflet. These findings suggest distinct functional roles for the two leaflets modulated by asymmetric lateral stress. Additionally, comparing the phase behavior of asymmetric and fully scrambled PMs reveals a key determinant of domain size: intact PMs maintain nanoscale domains, whereas cell-derived giant PM vesicles, which have lost the strict lipid asymmetry, exhibit microscale domains.

Microtubules are essential cytoskeletal components with a broad range of functions in which the structure and dynamics of their plus-end tips play critical roles. Existing mechanistic models explain the tips curving dynamics in different ways: the allosteric model suggests that GTP hydrolysis induces conformational changes in tubulin subunits that destabilize the lattice, leading to protofilament curving and depolymerization, while the lattice model posits that GTP hydrolysis directly destabilizes the microtubule lattice. However, the effect of GTP hydrolysis on the curving dynamics of microtubule tips remains incompletely understood. In this study, we employed a multiscale modeling approach, combining all-atom molecular dynamics simulations with Brownian dynamics simulations, to investigate the relaxation of microtubule plus-end tips into curved configurations. Our results show that both GDP- and GTP-bound tips exhibit an outward bending of protofilaments into curved, ram's horn-like structures, characterized by a linear relationship between curvature and distance from the plus-end tip. These observations align with experimental cryo-ET images of microtubule plus-end tips in different nucleotide states. Collectively, our findings suggest that the outward bending of protofilaments at the plus-end tip is an intrinsic feature of microtubules, independent of the nucleotide state.

In this work, we developed a coarse-grained model for RNA that is compatible with the Martini 3 force field. The model is parameterized following the Martini philosophy combining the top-down and bottom-up approaches. The nonbonded interactions in the model are derived from the partitioning of nucleobases between polar and nonpolar solvents, along with calculations of the potential of mean force between bases. For bonded interactions, parameters were refined based on atomistic simulations of double-stranded RNA. Additionally, an elastic network was incorporated to maintain the structural integrity of complex RNA molecules, such as transfer RNA, and other specific RNA configurations. We present the implementation of the Martini 3 RNA model and demonstrate its ability to capture the properties of individual bases, single-stranded RNA, double-stranded RNA, and RNA-protein complexes. Compared to the Martini 2 version, the current model offers several key advantages. It is fully compatible with the updated Martini 3 force field, exhibits greater numerical stability-allowing for the successful simulation of larger RNA-protein complexes, such as ribosomes, using the standard Martini time step of 20 fs-and it demonstrates improved agreement with all-atom models and experimental data. This new RNA model enables realistic large-scale explicit-solvent molecular dynamics simulations of complex RNA-containing systems.