Cell membranes actively participate in the regulation of protein structure and function. In this work, we conduct molecular dynamics simulations to investigate how different membrane environments ...affect protein structure and function in the case of MthK, a potassium channel. We observe different ion permeation rates of MthK in membranes with different properties, and ascribe them to a shift of the conformational equilibrium between two states of the channel that differ according to whether a transmembrane helix has a kink. Further investigations indicate that two key residues in the kink region mediate a crosstalk between two gates at the selectivity filter and the central cavity, respectively. Opening of one gate eventually leads to closure of the other. Our simulations provide an atomistic model of how lipid-protein interactions affect the conformational equilibrium of a membrane protein. The gating mechanism revealed for MthK may also apply to other potassium channels.
Understanding the lateral organization in plasma membranes remains an open problem despite a large body of research. Model membranes with coexisting micrometer-size domains are routinely employed as ...simplified models of plasma membranes. Many molecular dynamics simulations have investigated phase separation in model membranes at the coarse-grained level, but atomistic simulations remain computationally challenging. We simulate DPPC:DOPC and DPPC:DOPC:cholesterol lipid bilayers to investigate phase transitions at temperatures from 310 to 270 K. In this temperature range, the binary mixture forms a liquid phase (Lα) and a coexistence of Lα and either gel or ripple phases. The ternary mixture forms a liquid disordered (Ld) phase and a coexistence of liquid ordered (Lo) and either Ld or gel phases. We quantify the coexisting phases and discuss their properties against the background of experimental results. We observe partial registration of growing domains in both mixtures. We characterize specific cholesterol–cholesterol and cholesterol–phospholipid interaction geometries underlying its increased partitioning and the smoothed phase transition in the ternary mixture compared to the binary mixture. By comparing coexisting domains with homogeneous bilayers of the same composition, we demonstrate how domain coexistence affects their properties. Our simulations provide important insights into the lipid–lipid interactions in model lipid bilayers and improve our understanding of the lateral organization in plasma membranes with higher compositional complexity.
Mechanosensitive channels sense mechanical forces in cell membranes and underlie many biological sensing processes
. However, how exactly they sense mechanical force remains under investigation
. The ...bacterial mechanosensitive channel of small conductance, MscS, is one of the most extensively studied mechanosensitive channels
, but how it is regulated by membrane tension remains unclear, even though the structures are known for its open and closed states
. Here we used cryo-electron microscopy to determine the structure of MscS in different membrane environments, including one that mimics a membrane under tension. We present the structures of MscS in the subconducting and desensitized states, and demonstrate that the conformation of MscS in a lipid bilayer in the open state is dynamic. Several associated lipids have distinct roles in MscS mechanosensation. Pore lipids are necessary to prevent ion conduction in the closed state. Gatekeeper lipids stabilize the closed conformation and dissociate with membrane tension, allowing the channel to open. Pocket lipids in a solvent-exposed pocket between subunits are pulled out under sustained tension, allowing the channel to transition to the subconducting state and then to the desensitized state. Our results provide a mechanistic underpinning and expand on the 'force-from-lipids' model for MscS mechanosensation
.
The hydrophobic gating model, in which ion permeation is inhibited by the hydrophobicity, rather than a physical occlusion of the nanopore, functions in various ion channels including potassium ...channels. Available research focused on the energy barriers for ion/water conduction due to the hydrophobicity, whereas how hydrophobic gating affects the function and structure of channels remains unclear. Here, we use potassium channels as examples and conduct molecular dynamics simulations to investigate this problem. Our simulations find channel activities (ion currents) highly correlated with cavity hydration level, implying insufficient hydration as a barrier for ion permeation. Enforced cavity dehydration successfully induces conformational transitions between known channel states, further implying cavity dewetting as a key step in the gating procedure of potassium channels utilizing different activation mechanisms. Our work reveals how the cavity dewetting is coupled to structural changes of potassium channels and how it affects channel activity. The conclusion may also apply to other ion channels.
Parameter estimation is a key concern for reliable and predictive models of biological systems. In this paper, we propose a multi-objective, multi-state optimization framework that allows multiple ...data sources to be incorporated into the parameter estimation process. This enables the model to better represent a diverse range of data from both within and outwith the training set; and to determine more biologically relevant parameter values for the model parameters. The framework is based on a multi-objective PSwarm implementation (MoPSwarm) and is validated via a case study on the ERK signalling pathway, in which significant advantages over the conventional single-state approach are demonstrated. Several variants of the framework are analyzed to determine the optimal configuration for convergence and solution quality.
Originating in the early 20th century, ultrasonic testing has found increasingly extensive applications in medicine, industry, and materials science. Achieving both a high signal-to-noise ratio and ...high efficiency is crucial in ultrasonic testing. The former means an increase in imaging clarity as well as the detection depth, while the latter facilitates a faster refresh of the image. It is difficult to balance these two indicators with a conventional short pulse to excite the probe, so in general handling methods, these two factors have a trade-off. To solve the above problems, coded excitation (CE) can increase the pulse duration and offers great potential to improve the signal-to-noise ratio with equivalent or even higher efficiency. In this paper, we first review the fundamentals of CE, including signal modulation, signal transmission, signal reception, pulse compression, and optimization methods. Then, we introduce the application of CE in different areas of ultrasonic testing, with a focus on industrial bulk wave single-probe detection, industrial guided wave detection, industrial bulk wave phased array detection, and medical phased array imaging. Finally, we point out the advantages as well as a few future directions of CE.
Projection imaging has been employed widely in many areas, such as x-ray radiography, due to its penetration power and ballistic geometry of their paths. However, its resolution limit remains a major ...challenge, caused by the conflict of source intensity and source size associated with image blurriness. A simple yet robust scheme has been proposed here to solve the problem. An unconventional square aperture, rather than the usual circular beam, is constructed, which allows for the straightforward deciphering of a blurred spot, to unravel hundreds originally hidden pixels. With numerical verification and experimental demonstration, our proposal is expected to benefit multiple disciplines, not limited to x-ray imaging.
Fast prediction of adsorption isotherms is of great importance in the structural characterization and property prediction of zeolites prior to the synthesis of the target zeolite. Here, we employ the ...feature learning (FL) method to simulate the adsorption isotherms through density functional theory data generation of binding strength of nitrogen molecule adsorption in zeolites. Three features, that is, the size of adsorption cavities, the geometry of the pore apertures, and the local geometric distortion, are identified to control the binding strength, qualitatively in terms of a polynomial generative model. The local distortion of the Si–O–Si linkage is correlated with the electrostatic polarization of the nitrogen molecule upon adsorption in the zeolite cage. The electrostatic polarization from local zeolite environment can be further adjusted by the Si/Al ratios and thus can enhance the binding strength even twice as the silicalite zeolites when Si/Al = 47. The predicted adsorption isotherms of MFI and MWW zeolites from the feature-learned binding energies are in qualitative agreement with the experimental Brunauer–Emmett–Teller detection data. For 200,429 zeolites, including 248 known zeolites reported in the International Zeolite Association (IZA), the predicted adsorption isotherms are classified into three groups, among which the zeolites with the medium-sized three-dimensional channel architectures are favorable for nitrogen adsorption. The proposed FL scheme is a practical tool to give a quick prediction of adsorption isotherms and high-throughput screening of porous materials for adsorption-related applications.
Abstract
Analogous to DNA methylation and histone modification, RNA modification, as another epigenetic layer, plays an important role in many diseases, especially in tumours. As the most common form ...of RNA modification, m
6
A methylation has attracted increasing research interest in recent years. m
6
A is catalysed by RNA methyltransferases METTL3, METTL14 and WTAP (writers), m
6
A is removed by the demethylases FTO and ALKBH5 (erasers) and interacts with m6A-binding proteins, such as YT521-B homology (YTH) domain-containing proteins. This article reviews recent studies on methylation modification of m
6
A in gastrointestinal tract cancers.
This review highlights the effectiveness and robust nature of eco-friendly room-temperature polymerization initiated in emulsions, and some of its applications in polymer and materials science. The ...polymerization in emulsions initiated through a thermal or redox approach can be safely conducted under ambient conditions without using other hazardous chemicals. Thermal initiators decompose efficiently at the surfactant-stabilized oil-water interfaces at room temperature. The interface-induced initiation is found to be somewhat independent of surfactant type, insensitive to oxygen, and works for several thermal initiators. Redox initiators without transition metal compounds also effectively initiate room-temperature polymerization in emulsions. With the assistance of room temperature initiation, the polymers synthesized at room temperature are of high molecular mass. In addition, room-temperature polymerization allows temperature-sensitive molecules, for example, proteins and enzymes, to be incorporated with the polymers in situ. The applications of room-temperature polymerization in high internal phase emulsions and biomedicine are also discussed. The initiation of radicals from oil-water interfaces or transition metal-free redox systems is a promising eco-friendly method to promote radical reactions at room temperature.
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