Single-Channel Permeability from Markovian Milestoning, Umbrella Sampling, and Voltage Simulations

Permeations of ions and small molecules through membrane channels have diverse functions within cells. Various all-atom molecular dynamics (MD) simulations methods have been developed for computing free energy and crossing rate of permeants. However, a systemic comparison across different methods is scarce. Here, using a carbon nanotube as a model of small conductance (~2 pS) ion channel, we systemically compared three classes of MD-based approaches for computing single-channel permeability for potassium ion: equilibrium free energy-based approach using umbrella sampling, rare-even sampling approach using Markovian milestoning, and steady-state approach using applied voltages. The consistent kinetic results from all three methods demonstrated the robustness of MD-based methods in computing ion channel permeation. Two solvent boundary conditions are tested for milestoning and yield consistent forward and backward mean first passage time (MFPT). The advantages and disadvantages of each method are discussed, with the focus on the future applications of milestoning in more complex systems.

A tool for computation of changes in Na+, K+, Cl− channels and transporters due to apoptosis by data on cell ion and water content alteration

The study aims to know how the apoptotic alteration of cell ionic balance follows from the quantitatively characterised time dependent decrease in the sodium pump rate constant and changes in permeability coefficients of Cl−, K+, and Na+ channels. New experimental data on changes in cell K+, Na+, Cl−, water contents, and the Na+/ K+-ATPase-mediated K+ influx during the first 4 h of the staurosporine (STS) induced apoptosis are used as a basis for quantitative characterisation of channels and transporters responsible for apoptotic cell ion balance alteration. New computational tool is developed. It is found that the dynamics of alteration of ion and water balance in the studied U937 cells were associated with the decrease in the Na+/K+-ATPase rate coefficient by 2.2 times for 4 h, and a time-dependent increase in potassium channel permeabilitry, and a decrease in the sodium channel permeability, whereas the early decrease in [Cl−]i and cell volume were associated with an approximately 5-fold increase in the chloride channel permeability. The developed approach and the provided executable file can be used to identify the channels and transporters responsible for alterations of cell ion and water balance not only during apoptosis but in other physiological scenarios.

CLINIC AND THERAPEUTIC ASPECTS IN DUCTUS-DEPENDENT CONGENITAL HEART DEFECTS (PART II)

The cardiac congenital malformations with duct dependent pulmonary circulation are cardiopathies with severe neonatal manifestations and quickly progressive hemodynamic degradation. The obvious semeiology at the birth requires an appropriate diagnostic and an early therapeutic management through the maintenance of the arterial channel permeability.