The free energy governing K(+) conduction through gramicidin A channels is characterized by using over 0.1 micros of all-atom molecular dynamics simulations with explicit solvent and membrane. results provide encouraging agreement experiments insights into the permeation mechanism. surface K(+), as a function both axial radial coordinates, calculated. Correcting for simulation artifacts due to periodicity lack hydrocarbon polarizability, calculated single-channel conductance ions 0.8 pS,...

The basic amino acids lysine (Lys) and arginine (Arg) play important roles in membrane protein activity, the sensing of voltages, actions antimicrobial, toxin, cell-penetrating peptides. These are thought to stem from strong interactions disruptive influences these on lipid membranes. In this study, we employ fully atomistic molecular dynamics simulations observe, quantify, compare Lys Arg with saturated phosphatidylcholine membranes different thickness. We make use both charged...

Biological membranes consist of bilayer arrangements lipids forming a hydrophobic core that presents physical barrier to all polar and charged molecules. This long-held notion has recently been challenged by biological translocon-based experiments report small apparent free energies insert side chains near the center transmembrane (TM) helix. We have carried out fully atomistic simulations provide free-energy profile for moving TM helix containing protonated Arg chain across lipid bilayer....

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...

Proteins, including ion channels, often are described in terms of some average structure and pictured as rigid entities immersed a featureless solvent continuum. This simplified view, which provides for convenient representation the protein's overall structure, incurs risk deemphasizing important features underlying protein function, such thermal fluctuations atom positions discreteness molecules. These factors become particularly case movement through narrow pores, where magnitude may be...

We employ the entire experimentally determined protein structure for KcsA potassium channel from Streptomyces lividans in molecular dynamics calculations to observe hydrated structure, ion solvation, selectivity, multiple configurations, and diffusion. Free energy perturbation display a significant discrimination of ∼9 kT favor larger K+ ion. The forming is very flexible yet unable fully solvate Na+ because its smaller size large solvation energy. There evidence that acidic basic sidechains...

The issue of ionizable protein side chains interacting with lipid membranes has been the focus much attention since proposal paddle model voltage-gated ion channels, which suggested multiple arginine (Arg) may move through hydrocarbon core a membrane. Recent cell biology experiments have also interpreted to suggest that these would face only small free energy penalties cross membranes, challenging long-standing view in membrane biophysics. Here, we employ chain analog and transmembrane helix...

Ionizable amino acid side chains play important roles in membrane protein structure and function, including the activation of voltage-gated ion channels, where it has been previously suggested that charged may move through hydrocarbon core membrane. However, all-atom molecular dynamics simulations have demonstrated large free energy barriers for such lipid-exposed motions. These also revealed will deform due to presence a chain, leading complex solvation microenvironment which empirical...

The mechanism by which K + channels select for over Na ions has been debated the better part of a century. prevailing view is that contain highly conserved sites selectively bind through optimal coordination. We demonstrate series alternating within KcsA channel selectivity filter exists, are thermodynamically selective either (cage made from two planes oxygen atoms) or (a single plane four atoms). By combining Bennett free energy perturbation calculations with umbrella sampling, we show...

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...

Pentameric ligand-gated ion channels control synaptic neurotransmission by converting chemical signals into electrical signals. Agonist binding leads to rapid signal transduction via an allosteric mechanism, where global protein conformational changes open a pore across the nerve cell membrane. We use all-atom molecular dynamics with swarm-based string method solve for minimum free-energy gating pathways of proton-activated bacterial GLIC channel. describe stable wetted/open and...