K+-channels are membrane proteins that regulate the selective conduction of potassium ions across cell membranes. Although the atomic mechanisms of K+ permeation have been extensively investigated, previous work focused on characterizing the selectivity and occupancy of the binding sites, the role of water molecules in the conduction process, or the identification of the minimum energy pathways enabling permeation. Here, we exploit molecular dynamics simulations and the analytical power of Markov state models to perform a comparative study of ion conduction in three distinct channel models. Significant differences emerged in terms of permeation mechanisms and binding site occupancy by potassium ions and/or water molecules from 100 μs cumulative trajectories. We found that, at odds with the current paradigm, each system displays a characteristic permeation mechanism, and thus, there is not a unique way by which potassium ions move through K+-channels. The high functional diversity of K+-channels can be attributed in part to the differences in conduction features that have emerged from this work. This study provides crucial information and further inspiration for wet-lab chemists designing new synthetic strategies to produce versatile artificial ion channels that emulate membrane transport for their applications in diagnosis, sensors, the next generation of water treatment technologies, etc., as the ability of synthetic channels to transport molecular ions across a bilayer in a controlled way is usually governed through the choice of metal ions, their oxidation states, or their coordination geometries.
The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative CC bond-forming event turned out to be the rate-determining step.
In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields. Here, we systematically assessed the performance of the most popular force fields employed to study ion channels at timescales that are orders of magnitude greater than the ones accessible when these energy functions were first developed. Using 32 μs of trajectories, we investigated the dynamics of a member of the K2P ion channel family, the TRAAK channel, using two established force fields in simulations of biological systems: AMBER and CHARMM. We found that while results are comparable on the nanosecond timescales, significant inconsistencies arise at microsecond timescales.
Two-pore domain channels control cell excitability by modulating background potassium currents in response to several physicochemical stimuli. Thanks to the many crystal structures available, the TRAAK channel is one of the most studied, but little is known about its functional dynamics. Here, we explore TRAAK functionality complementing molecular dynamics with Brownian dynamics in a multiscale-modeling framework. We identify potential states of the channel that can prevent ion conduction, and we demonstrate that the suppression of currents is consistent with the presence of lipids inside the cavity.
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