How could simulations elucidate Nav1.5 channel blockers mechanism?

Tao and Corry used metadynamics, an enhanced sampling method to identify and classify Nav channel blockers.

Structural basis of human NOX5 activation.

NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear.

A structurally precise mechanism links an epilepsy-associated potassium channel mutation to interneuron dysfunction.

De novo heterozygous variants in encoding the voltage-gated potassium (K) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in c.

The dynamic interplay of PIP and ATP in the regulation of the K channel.

ATP-sensitive potassium (K ) channels couple the intracellular ATP concentration to insulin secretion. K channel activity is inhibited by ATP binding to the Kir6.2 tetramer and activated by phosphatidylinositol 4,5-bisphosphate (PIP ).

Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP.

Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP). Previous studies have demonstrated that PIP increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP remain unclear. Here, we used coarse-grained molecular dynamics and atomistic molecular dynamics simulations to model the PIP-binding site on both the up and down state conformations of TREK-1.

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid interactions surrounding a membrane protein are often identified in molecular dynamics (MD) simulations and are, increasingly, resolved in cryo-electron microscopy (cryo-EM) densities. Determining the relative importance of specific interaction sites is aided by determination of lipid binding affinities using experimental or simulation methods.

An outer-pore gate modulates the pharmacology of the TMEM16A channel.

TMEM16A Ca-activated chloride channels are involved in multiple cellular functions and are proposed targets for diseases such as hypertension, stroke, and cystic fibrosis. This therapeutic endeavor, however, suffers from paucity of selective and potent modulators. Here, exploiting a synthetic small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we shed light on sites of the channel amenable for pharmacological intervention.

From Bench to Biomolecular Simulation: Phospholipid Modulation of Potassium Channels.

Potassium (K) ion channels are crucial in numerous cellular processes as they hyperpolarise a cell through K conductance, returning a cell to its resting potential. K channel mutations result in multiple clinical complications such as arrhythmia, neonatal diabetes and migraines. Since 1995, the regulation of K channels by phospholipids has been heavily studied using a range of interdisciplinary methods such as cellular electrophysiology, structural biology and computational modelling.

Cryo-EM Structures of CusA Reveal a Mechanism of Metal-Ion Export.

Gram-negative bacteria utilize the resistance-nodulation-cell division (RND) superfamily of efflux pumps to expel a variety of toxic compounds from the cell. The CusA membrane protein, which recognizes and extrudes biocidal Cu(I) and Ag(I) ions, belongs to the heavy-metal efflux (HME) subfamily of RND efflux pumps. We here report four structures of the trimeric CusA heavy-metal efflux pump in the presence of Cu(I) using single-particle cryo-electron microscopy (cryo-EM).

Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease.

Membrane proteins are frequently modulated by specific protein-lipid interactions. The activation of human inward rectifying potassium (hKir) channels by phosphoinositides (PI) has been well characterised. Here, we apply a coarse-grained molecular dynamics free-energy perturbation (CG-FEP) protocol to capture the energetics of binding of PI lipids to hKir channels.

New insights into K channel gene mutations and neonatal diabetes mellitus.

The ATP-sensitive potassium channel (K channel) couples blood levels of glucose to insulin secretion from pancreatic β-cells. K channel closure triggers a cascade of events that results in insulin release. Metabolically generated changes in the intracellular concentrations of adenosine nucleotides are integral to this regulation, with ATP and ADP closing the channel and MgATP and MgADP increasing channel activity.