TAREK, M. | Search bioRxiv

bioRxiv2021

Molecular determinants of the modulation of the VSD-PD coupling mechanism of the KV7.1 channel by the KCNE1 ancillary subunits

The IKS current is diffused through the plasma membranes of cardiomyocytes during the last phase of the cardiac action potential. This repolarization current is conducted by a tetrameric protein complex derived from the co-expression of four voltage-gated potassium channel KV7.1 -subunits and KCNE1 ancillary subunits from KCNQ1 and KCNE1 genes, respectively. We studied here the conformational space of KV7.1 in presence and absence of KCNE1, by building transmembrane models of their known Resting, Intermediate, and Activated states. We conducted Molecular Dynamics simulations of these models in lipid bilayers including the phosphatidyl-inositol-4,5-bisphosphate (PIP2) lipids. The comparative analysis of MD trajectories obtained for the KV7.1 and IKS models reveals how KCNE1 shifts the coupling mechanism between the activation state of the Voltage Sensor Domain of the channel and the conformation (open or closed) of its Pore Domain.

biophysics↗

bioRxiv2020

On the permeability of cell membranes subjected to lipid oxidation

The formation of transient hydrophilic pores in their membranes is a well-recognized mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores alone is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for the sustained permeability of cell membranes, which persist long after the pulses application, remain elusive. The complete resealing of the cell membranes takes indeed orders of magnitude longer than the time of electropore closure as reported from molecular modelling investigations. A possible alternative mechanism to explain the observed long-lived permeability of cell membranes, lipid peroxidation, has been previously suggested but the theoretical investigations of membrane lesions, containing excess amounts of hydroperoxides, have shown that the conductivities of such lesions were not high enough to reasonably explain the entire range of experimental measurements. Here, we expand on these studies and investigate the permeability of cell membrane lesions that underwent secondary oxidation. Molecular dynamics simulations and free energy calculations on lipid bilayers in different states show that such lesions provide a better model for post-pulsed permeable and conductive electropermeabilized cells. These results are further discussed in context of sonoporation and ferroptosis, respectively a procedure and a phenomena, among others, in which alike electroporation substantial lipid oxidation might be triggered. HighlightsO_LIThe contribution of secondary lipids oxidation to the permeabilization of model membranes is quantitatively assessed C_LIO_LISmall patches of secondary lipids oxidation cause formation long-lived pores in lipid bilayers. C_LIO_LIThe cholesterol content of membranes enhances the life-time of the formed pores. C_LIO_LIA single pore accounts for the measured post-pulse electropermeabilization of cells. C_LIO_LIThe diffusion of the secondary oxidation lipids, even after pores closure leads to permeability of lipid membrane. C_LI

biophysics↗

bioRxiv2017

Exploring the Complex Dynamics of an Ion Channel Voltage Sensor Domain via Computation

Voltage-gated ion channels are ubiquitous proteins that orchestrate electrical signaling across excitable membranes. Key to their function is activation of the voltage sensor domain (VSD), a transmembrane four alpha-helix bundle that triggers channel opening. Modeling of currents from electrophysiology experiments yields a set of kinetic parameters for a given channel, but no direct molecular insight. Here we use molecular dynamics (MD) simulations to determine the free energy landscape of VSD activation and to, ultimately, predict the time evolution of the resulting gating currents. Our study provides the long-sought-for bridge between electrophysiology and microscopic molecular dynamics and confirms, as already suggested on the basis of experiments, that rate-limiting barriers play a critical role in activation kinetics.

biophysics↗