SPECIAL TOPIC — Soft matter and biological physics null
Cyclin-dependent kinases (CDKs) are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan-CDK inhibitors bind to the highly conserved catalytic ATP-binding pocket and therefore lack the specificity to prevent side effects. It is desirable to develop drugs targeting non-catalytic pockets for specificity towards individual CDKs. Here we performed a systematic analysis of non-catalytic pockets on CDKs and identified a region underneath the T-loop, which we term TL pocket, for potential inhibitor development. Specifically, we compared the TL pockets of human CDK2 and CDK7-homolog Pfmrk of Plasmodium falciparum, a malaria-causing parasite. Molecular dynamics simulations of several short peptides revealed that this less conserved TL pocket could be used to design potentially specific inhibitors against malaria disease.
Nanostructures self-assembled by cross-β peptides with ordered structures and advantageous mechanical properties have many potential applications in biomaterials and nanotechnologies. Quantifying the intra-and inter-molecular driving forces for peptide self-assembly at the atomistic level is essential for understanding the formation mechanism and nanomechanics of various morphologies of self-assembled peptides. We investigate the thermodynamics of the intra-and inter-sheet structure formations in the self-assembly process of cross-β peptide KⅢIK by means of steered molecular dynamics simulation combined with umbrella sampling. It is found that the mechanical properties of the intra-and inter-sheet structures are highly anisotropic with their intermolecular bond stiffness at the temperature of 300 K being 5.58 N/m and 0.32 N/m, respectively. This mechanical anisotropy comes from the fact that the intra-sheet structure is stabilized by enthalpy but the inter-sheet structure is stabilized by entropy. Moreover, the formation process of KⅢIK intra-sheet structure is cooperatively driven by the van der Waals (VDW) interaction between the hydrophobic side chains and the electrostatic interaction between the hydrophilic backbones, but that of the inter-sheet structure is primarily driven by the VDW interaction between the hydrophobic side chains. Although only peptide KⅢIK is studied, the qualitative conclusions on the formation mechanism should also apply to other cross-β peptides.
The biexponential distributions of open times are observed in various types of ion channels. In this paper, by discussing a simple channel model, we show that there are two different schemes to understand the biexponential distribution of open times. One scheme is mathematically strict based on generator matrix theory, while the other one has a clear physical explanation according to an approximation process with numerical simulation of Markovian channel dynamics. Our comparison results suggest that even for biologically complex channels, in addition to carrying out a stochastic simulation, the strict theoretical analysis should be considered to understand the multiple exponential distributions of open times.
Research on protein-membrane interactions has been undeveloped due to the lack of proper techniques to detect the position of proteins at membranes because membranes are usually only about 4-nm thick. We have recently developed a new method named surface-induced fluorescence attenuation (SIFA) to track both vertical and lateral kinetics of a single labelling dye in supported lipid bilayers. It takes advantage of strong interaction between a light-emitting dye and a partially reflecting surface. By applying the technique to membrane proteins being fluorescently labelled at different residues, here we show that SIFA can measure not only the insertion depth of a dye inside a lipid bilayer, but also the position of a dye in solution near the surface. SIFA can therefore be used to study membrane proteins of various types.
In the present study, a fast chemical shift imaging (CSI) method has been used to dynamically monitor the formation of oil-water emulsions and the phase separation process of the emulsion phase from the excessive water or oil phase on the molecular level. With signals sampled from series of small voxels simultaneously within a few seconds, high-resolution one-dimensional (1D) 1H nuclear magnetic resonance (NMR) spectra from different spatial positions for inhomogeneous emulsion systems induced by susceptibility differences among components can be obtained independently. On the basis of integrals from these 1H NMR spectra, profiles obtained explicitly demonstrate the spatial and temporal variations of oil concentrations. Furthermore, the phase separation time and the length of the oil-water emulsion phase are determined. In addition, effects of oil types and proportions of the emulsifier on the emulsification states are also inspected. Experimental results indicate that 1D PHASICS (Partial Homogeneity Assisted Inhomogeneity Correction Spectroscopy) provides a helpful and promising alternative to research on dynamic processes or chemical reactions.
Cell migration plays an essential role in a wide variety of physiological and pathological processes. In this paper we numerically discuss the properties of an anisotropic persistent random walk (APRW) model, in which two different and independent persistent times are assumed for cell migrations in the x-and y-axis directions. An intrinsic orthogonal coordinates with the primary and non-primary directions can be defined for each migration trajectory based on the singular vector decomposition method. Our simulation results show that the decay time of single exponential distribution of velocity auto-correlation function (VACF) in the primary direction is actually the large persistent time of the APRW model, and the small decay time of double exponential VACF in the non-primary direction equals the small persistent time of the APRW model. Thus, we propose that the two persistent times of anisotropic migration of cells can be properly estimated by discussing the VACFs of trajectory projected to the primary and non-primary directions.
We present an extended analytical model including the depletion effect and the dimension of ligand-receptor complex, aiming to elucidate their influences on endocytosis of spherocylindrical nanoparticles (NPs). It is found that the dimension of ligand-receptor complex (δ) and the depletion effect interrelatedly govern the optimal conditions of NP endocytosis. The endocytosis phase diagram constructed in the space of NP radius and relative aspect ratio indicates that the endocytosis of NP is enhanced evidently by reducing the optimal radius and the threshold radius of endocytosed NP. Meanwhile, through thermodynamic and kinetic analysis of the diffusion of receptors, the dependence of diffusion length on depletion effect and the dimension of ligand-receptor complex can be identified in great detail. For small aspect ratio, diffusion length decreases with increasing concentration c of small bioparticles in cellular environment. Endocytosis speed corresponding to large radius R and high concentration c of small bioparticles strongly depends on the increasing (2r-δ). These results may show some highlights into the conscious design of NPs for diagnostic agents and therapeutic drug delivery applications.
The tumor suppressor p53 mediates the cellular response to various stresses. It was experimentally shown that the concentration of p53 can show oscillations with short or long periods upon DNA damage. The underlying mechanism for this phenomenon is still not fully understood. Here, we construct a network model comprising the ATM-p53-Wip1 and p53-Mdm2 negative feedback loops and ATM autoactivation. We recapitulate the typical features of p53 oscillations including p53 birhythmicity. We show the dependence of p53 birhythmicity on various factors such as the phosphorylation status of ATM. We also perform stochastic simulation and find the noise-induced transitions between two modes of p53 oscillation, which increases the p53 variability in both the amplitude and period. These results suggest that p53 birhythmicity enhances the responsiveness of p53 network, which may facilitate its tumor suppressive function.