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https://www.readbyqxmd.com/read/28528671/voltage-gated-sodium-channel-pharmacology-insights-from-molecular-dynamics-simulations
#1
Rong Chen, Amanda Buyan, Ben Corry
Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28508424/computational-site-directed-mutagenesis-studies-of-the-role-of-the-hydrophobic-triad-on-substrate-binding-in-cholesterol-oxidase
#2
Laith Hisham Harb, Mahreen Arooj, Alice Vrielink, Ricardo L Mancera
Cholesterol oxidase (ChOx) is a flavoenzyme that oxidises and isomerises cholesterol (CHL) to form cholest-4-en-3-one. Molecular docking and molecular dynamics simulations were conducted to predict the binding interactions of CHL in the active site. Several key interactions (E361-CHL, N485-FAD and H447-CHL) were identified and which are likely to determine the correct positioning of CHL relative to flavin-adenine dinucleotide (FAD). Binding of CHL also induced changes in key residues of the active site leading to the closure of the oxygen channel...
May 15, 2017: Proteins
https://www.readbyqxmd.com/read/28504641/helical-jackknives-control-the-gates-of-the-double-pore-k-uptake-system-ktrab
#3
Marina Diskowski, Ahmad Reza Mehdipour, Dorith Wunnicke, Deryck J Mills, Vedrana Mikusevic, Natalie Bärland, Jan Hoffmann, Nina Morgner, Heinz-Jürgen Steinhoff, Gerhard Hummer, Janet Vonck, Inga Haenelt
Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukaryotic and most bacterial ligand-gated K(+) channels, RCK domains regulate ion fluxes. Until now, a single regulatory mechanism has been proposed for all RCK-regulated channels, involving signal transduction from the RCK domain to the gating area. Here we present an inactive ADP-bound structure of KtrAB from Vibrio alginolyticus, determined by cryo-electron microscopy, which, combined with EPR spectroscopy and molecular dynamics simulations, uncovers a novel regulatory mechanism for ligand-induced action at a distance...
May 15, 2017: ELife
https://www.readbyqxmd.com/read/28499087/identification-of-intra-helical-bifurcated-h-bonds-as-a-new-type-of-gate-in-k-channels
#4
Oliver Rauh, Martin Urban, Leonhard M Henkes, Tobias Winterstein, Timo Greiner, James L Van Etten, Anna Moroni, Stefan M M Kast, Gerhard Thiel, Indra Schroeder
Gating of ion channels is based on structural transitions between open and closed states. To uncover the chemical basis of individual gates, we performed a comparative experimental and computational analysis between two K+ channels, KcvS and KcvNTS. These small viral encoded K+ channel proteins, with a monomer size of only 82 amino acids, resemble the pore module of all complex K+ channels in terms of structure and function. Even though both proteins share about 90% amino acid sequence identi-ty they exhibit different open probabilities with ca...
May 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28494157/side-fenestrations-provide-an-anchor%C3%A2-for-a-stable-binding-of-a1899-to-the-pore-of-task-1-potassium-channels
#5
David Ramirez, Bárbara Arévalo, Gonzalo Martínez, Susanne Rinné, Francisco V Sepúlveda, Niels Decher, Wendy González
A1899 is a potent and selective inhibitor of the two-pore domain potassium (K2P) channel TASK-1. It was previously reported that A1899 acts as an open-channel blocker and binds to residues of the P1, P2 regions, the M2, M4 segments and the halothane response element. The recently described crystal structures of K2P channels together with the newly identified side-fenestrations indicate that residues relevant for TASK-1 inhibition are not purely facing the central cavity as initially proposed. Accordingly, the TASK-1 binding site and the mechanism of inhibition might need a re-evaluation...
May 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28489071/exchange-pathways-of-plastoquinone-and-plastoquinol-in-the-photosystem-ii-complex
#6
Floris J Van Eerden, Manuel N Melo, Pim W J M Frederix, Xavier Periole, Siewert J Marrink
Plastoquinone (PLQ) acts as an electron carrier between photosystem II (PSII) and the cytochrome b6f complex. To understand how PLQ enters and leaves PSII, here we show results of coarse grained molecular dynamics simulations of PSII embedded in the thylakoid membrane, covering a total simulation time of more than 0.5 ms. The long time scale allows the observation of many spontaneous entries of PLQ into PSII, and the unbinding of plastoquinol (PLQol) from the complex. In addition to the two known channels, we observe a third channel for PLQ/PLQol diffusion between the thylakoid membrane and the PLQ binding sites...
May 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28485920/bacterial-outer-membrane-porins-as-electrostatic-nanosieves-exploring-transport-rules-of-small-polar-molecules
#7
Harsha Bajaj, Silvia Acosta Gutierrez, Igor Bodrenko, Giuliano Malloci, Mariano Andrea Scorciapino, Mathias Winterhalter, Matteo Ceccarelli
Transport of molecules through biological membranes is a fundamental process in biology, facilitated by selective channels and general pores. The architecture of some outer membrane pores in Gram-negative bacteria, common to other eukaryotic pores, suggests them as prototypes of electrostatically regulated nanosieve devices. In this study, we sensed the internal electrostatics of the two most abundant outer membrane channels of Escherichia coli, using norfloxacin as a dipolar probe in single molecule electrophysiology...
May 9, 2017: ACS Nano
https://www.readbyqxmd.com/read/28482186/reaction-mechanism-of-sterol-hydroxylation-by-steroid-c25-dehydrogenase-homology-model-reactivity-and-isoenzymatic-diversity
#8
Agnieszka Rugor, Anna Wójcik-Augustyn, Ewa Niedzialkowska, Stefan Mordalski, Jakub Staroń, Andrzej Bojarski, Maciej Szaleniec
Steroid C25 dehydrogenase (S25DH) is a molybdenum-containing oxidoreductase isolated from the anaerobic Sterolibacterium denitrificans Chol-1S. S25DH is classified as 'EBDH-like' enzyme (EBDH, ethylbenzene dehydrogenase) and catalyzes the introduction of an OH group to the C25 atom of a sterol aliphatic side-chain. Due to its regioselectivity, S25DH is proposed as a catalyst in production of pharmaceuticals: calcifediol or 25-hydroxycholesterol. The aim of presented research was to obtain structural model of catalytic subunit α and investigate the reaction mechanism of the O2-independent tertiary carbon atom activation...
April 27, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28472884/probing-the-effects-of-gating-on-the-ion-occupancy-of-the-k-channel-selectivity-filter-using-two-dimensional-infrared-spectroscopy
#9
Huong T Kratochvil, Michał Maj, Kimberly Matulef, Alvin W Annen, Jared Ostmeyer, Eduardo Perozo, Benoît Roux, Francis I Valiyaveetil, Martin T Zanni
The interplay between the intracellular gate and the selectivity filter underlies the structural basis for gating in potassium ion channels. Using a combination of protein semisynthesis, two-dimensional infrared (2D IR) spectroscopy, and molecular dynamics (MD) simulations, we probe the ion occupancy at the S1 binding site in the constricted state of the selectivity filter of the KcsA channel when the intracellular gate is open and closed. The 2D IR spectra resolve two features, whose relative intensities depend on the state of the intracellular gate...
May 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28445755/mapping-ryanodine-binding-sites-in-the-pore-cavity-of-ryanodine-receptors
#10
Van A Ngo, Laura L Perissinotti, Williams Miranda, S R Wayne Chen, Sergei Y Noskov
Ryanodine (Ryd) irreversibly targets ryanodine receptors (RyRs), a family of intracellular calcium release channels essential for many cellular processes ranging from muscle contraction to learning and memory. Little is known of the atomistic details about how Ryd binds to RyRs. In this study, we used all-atom molecular dynamics simulations with both enhanced and bidirectional sampling to gain direct insights into how Ryd interacts with major residues in RyRs that were experimentally determined to be critical for its binding...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28433036/an-eqt-based-cdft-approach-for-thermodynamic-properties-of-confined-fluid-mixtures
#11
M H Motevaselian, N R Aluru
We present an empirical potential-based quasi-continuum theory (EQT) to predict the structure and thermodynamic properties of confined fluid mixtures. The central idea in the EQT is to construct potential energies that integrate important atomistic details into a continuum-based model such as the Nernst-Planck equation. The EQT potentials can be also used to construct the excess free energy functional, which is required for the grand potential in the classical density functional theory (cDFT). In this work, we use the EQT-based grand potential to predict various thermodynamic properties of a confined binary mixture of hydrogen and methane molecules inside graphene slit channels of different widths...
April 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28433027/potential-of-mean-force-for-insertion-of-antimicrobial-peptide-melittin-into-a-pore-in-mixed-dopc-dopg-lipid-bilayer-by-molecular-dynamics-simulation
#12
Yuan Lyu, Ning Xiang, Xiao Zhu, Ganesan Narsimhan
Antimicrobial peptides (AMPs) inactivate microorganisms by forming transmembrane pores in a cell membrane through adsorption and aggregation. Energetics of addition of an AMP to a transmembrane pore is important for evaluation of its formation and growth. Such information is essential for the characterization of pore forming ability of peptides in cell membranes. This study quantifies the potential of mean force through molecular dynamics (MD) simulation for the addition of melittin, a naturally occurring AMP, into a DOPC/DOPG mixed bilayer, a mimic of bacterial membrane, for different extents of insertion into either a bilayer or a pore consisting of three to six transmembrane peptides...
April 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28432359/role-of-the-ion-channel-extracellular-collar-in-ampa-receptor-gating
#13
Maria V Yelshanskaya, Samaneh Mesbahi-Vasey, Maria G Kurnikova, Alexander I Sobolevsky
AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28430444/molecular-structuring-and-percolation-transition-in-hydrated-sulfonated-poly-ether-ether-ketone-membranes
#14
Madhusmita Tripathy, P B Sunil Kumar, Abhijit P Deshpande
The extent of phase separation and water percolation in sulfonated membranes are the key to their performance in fuel cells. Toward this, the effect of hydration on the morphology and transport characteristics of sulfonated poly(ether ether ketone), sPEEK, membrane is investigated using atomistic molecular dynamics simulation at various hydration levels(λ: number of water molecules per sulfonate group). The evolution of local morphology is investigated using structural correlations and minimum pair distances...
May 11, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28428758/modulation-of-asymmetric-flux-in-heterotypic-gap-junctions-by-pore-shape-particle-size-and-charge
#15
Abhijit Mondal, Frank B Sachse, Alonso P Moreno
Gap junction channels play a vital role in intercellular communication by connecting cytoplasm of adjoined cells through arrays of channel-pores formed at the common membrane junction. Their structure and properties vary depending on the connexin isoform(s) involved in forming the full gap junction channel. Lack of information on the molecular structure of gap junction channels has limited the development of computational tools for single channel studies. Currently, we rely on cumbersome experimental techniques that have limited capabilities...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28415275/effects-of-surface-roughness-on-shear-viscosity
#16
Michail Papanikolaou, Michael Frank, Dimitris Drikakis
This paper investigates the effect of surface roughness on fluid viscosity using molecular dynamics simulations. The three-dimensional model consists of liquid argon flowing between two solid walls whose surface roughness was modeled using fractal theory. In tandem with previously published experimental work, our results show that, while the viscosity in smooth channels remains constant across the channel width, in the presence of surface roughness it increases close to the walls. The increase of the boundary viscosity is further accentuated by an increase in the depth of surface roughness...
March 2017: Physical Review. E
https://www.readbyqxmd.com/read/28410930/ligand-diffusion-in-proteins-via-enhanced-sampling-in-molecular-dynamics
#17
REVIEW
J Rydzewski, W Nowak
Computational simulations in biophysics describe the dynamics and functions of biological macromolecules at the atomic level. Among motions particularly important for life are the transport processes in heterogeneous media. The process of ligand diffusion inside proteins is an example of a complex rare event that can be modeled using molecular dynamics simulations. The study of physical interactions between a ligand and its biological target is of paramount importance for the design of novel drugs and enzymes...
April 1, 2017: Physics of Life Reviews
https://www.readbyqxmd.com/read/28409218/transmembrane-helices-containing-a-charged-arginine-are-thermodynamically-stable
#18
Martin B Ulmschneider, Jakob P Ulmschneider, J Alfredo Freites, Gunnar von Heijne, Douglas J Tobias, Stephen H White
Hydrophobic amino acids are abundant in transmembrane (TM) helices of membrane proteins. Charged residues are sparse, apparently due to the unfavorable energetic cost of partitioning charges into nonpolar phases. Nevertheless, conserved arginine residues within TM helices regulate vital functions, such as ion channel voltage gating and integrin receptor inactivation. The energetic cost of arginine in various positions along hydrophobic helices has been controversial. Potential of mean force (PMF) calculations from atomistic molecular dynamics simulations predict very large energetic penalties, while in vitro experiments with Sec61 translocons indicate much smaller penalties, even for arginine in the center of hydrophobic TM helices...
April 13, 2017: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/28409029/biophysical-approaches-facilitate-computational-drug-discovery-for-atp-binding-cassette-proteins
#19
REVIEW
Steven V Molinski, Zoltán Bozóky, Surtaj H Iram, Saumel Ahmadi
Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank...
2017: International Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28402882/gating-charge-calculations-by-computational-electrophysiology-simulations
#20
Jan-Philipp Machtens, Rodolfo Briones, Claudia Alleva, Bert L de Groot, Christoph Fahlke
Electrical cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the molecular details of voltage sensing remain insufficiently understood. Here, we present a molecular dynamics simulation-based method to determine the underlying charge movement across the membrane-the gating charge-by measuring electrical capacitor properties of membrane-embedded proteins. We illustrate the approach by calculating the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1...
April 11, 2017: Biophysical Journal
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