Voltage-gated Na(+) channels play an essential role in electrical signaling the nervous system and are key pharmacological targets for a range of disorders. The recent solution X-ray structures bacterial channel NavAb has provided opportunity to study functional mechanisms at atomic level. This channel's selectivity filter exhibits EEEE ring sequence, characteristic mammalian Ca(2+), not Na(+), channels. raises fundamentally important question: just what makes conduct ions? Here we explore...

Significance Voltage-gated sodium (Na v ) channels control neuronal signaling and are key targets for local anesthetics, antiepileptics, therapeutics a range of disorders. Multimicrosecond Anton simulations have provided completely unbiased molecular-level views the interactions lipophilic drugs with recently solved bacterial channel, Na Ab from Arcobacter butzleri . Newly parameterized benzocaine phenytoin molecules exhibit different membrane partition coefficients, crossing rates...

Increased extracellular proton concentrations during neurotransmission are converted to excitatory sodium influx by acid-sensing ion channels (ASICs). 10-fold sodium/potassium selectivity in ASICs has long been attributed a central constriction the channel pore, but experimental verification is lacking due sensitivity of this structure conventional manipulations. Here, we explored basis for incorporating unnatural amino acids into channel, engineering stoichiometry and performing free energy...

Potassium channels can become nonconducting via inactivation at a gate inside the highly conserved selectivity filter (SF) region near extracellular side of membrane. In certain ligand-gated channels, such as BK and MthK, Ca2+-activated K+ channel from Methanobacterium thermoautotrophicum, SF has been proposed to play role in opening closing rather than inactivation, although underlying conformational changes are unknown. Using X-ray crystallography, identical conductive MthK structures were...

Epithelial Na+ channel (ENaC)/degenerin family members are involved in mechanosensation, blood pressure control, pain sensation, and the expression of fear. Several these types display a form desensitization that allows to limit influx during prolonged stimulation. We used site-directed mutagenesis chemical modification, functional analysis, molecular dynamics simulations investigate role lower palm domain acid-sensing ion 1, member ENaC/degenerin family. The domains this trimeric arranged...

Bacterial and human voltage-gated sodium channels (Navs) exhibit similar cation selectivity, despite their distinct EEEE DEKA selectivity filter signature sequences. Recent high-resolution structures for bacterial Navs have allowed us to learn about ion conduction mechanisms in these simpler homo-tetrameric channels, but our understanding of the function mammalian counterparts remains limited. To probe mechanisms, a model Nav1.2 channel has been constructed by grafting residues its external...

Potassium channels are membrane proteins known to select potassium over sodium ions at a high diffusion rate. We conducted ab initio calculations on filter model of KcsA about 300 atoms the Hartree-Fock level theory. Partial charges were derived from quantum mechanically determined electrostatic potential either with Merz-Kollman or Hinsen-Roux schemes. Large polarization and/or charge transfer occur located in filter, while remain closer unity. As result, weaker binding is obtained for K+...

Trimeric acid-sensing ion channels (ASICs) contribute to neuronal signaling by converting extracellular acidification into excitatory sodium currents. Previous work with homomeric ASIC1a implicates conserved leucine (L7′) and consecutive glycine-alanine-serine (GAS belt) residues near the middle, negatively charged (E18′) at bottom of pore in permeation and/or selectivity. However, a mechanism selectivity throughout ASIC family has not been established. We therefore explored molecular...

Since the pioneering work of Zhou et al. (Y. Zhou, J. H. Morais-Cabral, A. Kaufman and R. MacKinnon, Nature, 2001, 414, 43-48) it is now well established that streptomyces lividans potassium channel (KcsA) can accommodate more than one ion, namely between 2 3. As a result, usually assumed conduction ions proceeds through barrier-less knock-on mechanism. This an alternation two sequences containing either or 3 which have nearly same energies. However, origin such mechanism not clearly known....

Molecular dynamics simulations supported by electrostatic calculations have been conducted on the KcsA channel to determine role of water molecules in pore. Starting from X-ray structure its closed state at 2.0 angstroms resolution, opening pore towards a conformation built basis EPR results is studied. We show that act as structural element for K+ ions inside filter and hydrophobic cavity channel. In filter, tends enhance depth wells occupied ions, while there strong correlation between...

The charge profile of K+ and Na+ ions moving in a single file across the filter KcsA channel is determined using both molecular dynamics simulations ab initio calculations. We show strong correlation between variation ion location resulting saw-tooth profile, which provides additional information on influence transfer permeation selectivity channel.

We performed in-depth analysis of the forces which act on K(+) ions in selectivity filter KcsA channel order to estimate relative importance static and dynamic influence wall water molecules ion permeation selectivity. The were computed using trajectories all-atom molecular dynamics simulations. It is shown that contributes about 3% net force acting can be neglected studies focused macroscopic properties channel, such as current. Among atoms, only pore-forming carbonyl groups considered...

The aim of this series papers is to develop the semi-quantitative theory gating KcsA channel.Methods.For purpose available structural and electrophysiological data results molecular dynamics simulations were used in context concept dynamical self-organization.In second paper we describe principles dynamic self-organization channel based on concept.Conclusions.Present work first successful attempt combining structure real protein general self-organization.

The aim of this series papers is to develop the semi-quantitative theory gating KcsA channel.For purpose available structural and electrophysiological data results molecular dynamics simulations were used in context concept dynamical self-organization.In first paper we describe simplified model geometry energetics process.This work successful attempt combining structure a real protein general dynamic self-organization.