Binding Modes and Functional Surface of Anti-mammalian Scorpion α-Toxins to Sodium Channels

Biochemistry ◽  
2012 ◽  
Vol 51 (39) ◽  
pp. 7775-7782 ◽  
Author(s):  
Rong Chen ◽  
Shin-Ho Chung
Keyword(s):  
Sodium Channels ◽  
Binding Modes ◽  
Functional Surface

scholarly journals Investigation of Binding Modes and Functional Surface of Scorpion Toxins ANEP to Sodium Channels 1.7

Toxins ◽  
2017 ◽  
Vol 9 (12) ◽  
pp. 387 ◽  
Author(s):  
Yongbo Song ◽  
Zeyu Liu ◽  
Qi Zhang ◽  
Chunming Li ◽  
Wei Jin ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Binding Modes ◽  
Scorpion Toxins ◽  
Functional Surface

scholarly journals Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

Marine Drugs ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. 510 ◽  
Author(s):  
Rocio K. Finol-Urdaneta ◽  
Jeffrey R. McArthur ◽  
Vyacheslav S. Korkosh ◽  
Sun Huang ◽  
Denis McMaster ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Cell Voltage ◽  
Hill Coefficient ◽  
Dependent Manner ◽  
Binding Modes ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Conducting Pathway

µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, thus preventing muscle contraction. Intriguingly, computer simulations predicted that PIIIA binds to prokaryotic channel NavAb with much higher affinity than to fish (and other vertebrates) skeletal muscle sodium channel (Nav 1.4). Here, using whole-cell voltage clamp, we demonstrate that PIIIA inhibits NavBac mediated currents even more potently than predicted. From concentration-response data, with [PIIIA] varying more than 6 orders of magnitude (10−12 to 10−5 M), we estimated an IC50 = ~5 pM, maximal block of 0.95 and a Hill coefficient of 0.81 for the inhibition of peak currents. Inhibition was stronger at depolarized holding potentials and was modulated by the frequency and duration of the stimulation pulses. An important feature of the PIIIA action was acceleration of macroscopic inactivation. Docking of PIIIA in a NaChBac (NavBh) model revealed two interconvertible binding modes. In one mode, PIIIA sterically and electrostatically blocks the permeation pathway. In a second mode, apparent stabilization of the inactivated state was achieved by PIIIA binding between P2 helices and trans-membrane S5s from adjacent channel subunits, partially occluding the outer pore. Together, our experimental and computational results suggest that, besides blocking the channel-mediated currents by directly occluding the conducting pathway, PIIIA may also change the relative populations of conducting (activated) and non-conducting (inactivated) states.

scholarly journals Common Features in the Functional Surface of Scorpion β-Toxins and Elements That Confer Specificity for Insect and Mammalian Voltage-gated Sodium Channels

2004 ◽  
Vol 280 (6) ◽  
pp. 5045-5053 ◽  
Author(s):  
Lior Cohen ◽  
Izhar Karbat ◽  
Nicolas Gilles ◽  
Nitza Ilan ◽  
Morris Benveniste ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Functional Surface ◽  
Voltage Gated ◽  
Common Features ◽  
Voltage Gated Sodium Channels

Alendronate Stimulates Expression of Functional Surface Molecules ICAM-1, HLA-DR, and B7-2 on Human Monocytes

2006 ◽  
Vol 15 (03) ◽  
pp. 188-196
Author(s):  
S. Brosch ◽  
M. Shehata ◽  
G. Hofbauer ◽  
M. Peterlik ◽  
P. Pietschmann
Keyword(s):  
Human Monocytes ◽  
Functional Surface ◽  
Surface Molecules ◽  
Hla Dr

Neuronal Sodium Channels in Neurodegeneration and Neuroprotection

2003 ◽  
Author(s):  
Frank C. Tortella ◽  
Keyword(s):  
Sodium Channels

Medullary epithelial sodium channels (ENAC) participate in cerebral blood flow (CBF) autoregulation

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S190-S190
Author(s):  
Eugene Golanov ◽  
Heather Drummond ◽  
Jasleen Shant ◽  
Benjamin Clower ◽  
Betty Chen
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sodium Channels ◽  
Epithelial Sodium Channels

Pyrethroids and voltage sensors in sodium channels

2016 ◽  
Author(s):  
Eugenio Eduardo Oliveira
Keyword(s):  
Sodium Channels ◽  
Voltage Sensors

On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

2020 ◽  
Author(s):  
Robert Stepic ◽  
Lara Jurković ◽  
Ksenia Klementyeva ◽  
Marko Ukrainczyk ◽  
Matija Gredičak ◽  
...  
Keyword(s):  
Active Sites ◽  
Realistic Model ◽  
Binding Energies ◽  
Inhibition Mechanism ◽  
Aqueous Environment ◽  
Binding Modes ◽  
Carboxylate Groups ◽  
Dissolved Ions ◽  
Living Organisms ◽  
Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

Reversibly Sampling Conformations and Binding Modes Using Molecular Darting

2020 ◽  
Author(s):  
Samuel C. Gill ◽  
David Mobley
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Sites ◽  
Degrees Of Freedom ◽  
Dynamics Simulation ◽  
Hiv Integrase ◽  
Binding Modes ◽  
System A ◽  
Multiple Binding ◽  
Internal Degrees Of Freedom

<div>Sampling multiple binding modes of a ligand in a single molecular dynamics simulation is difficult. A given ligand may have many internal degrees of freedom, along with many different ways it might orient itself a binding site or across several binding sites, all of which might be separated by large energy barriers. We have developed a novel Monte Carlo move called Molecular Darting (MolDarting) to reversibly sample between predefined binding modes of a ligand. Here, we couple this with nonequilibrium candidate Monte Carlo (NCMC) to improve acceptance of moves.</div><div>We apply this technique to a simple dipeptide system, a ligand binding to T4 Lysozyme L99A, and ligand binding to HIV integrase in order to test this new method. We observe significant increases in acceptance compared to uniformly sampling the internal, and rotational/translational degrees of freedom in these systems.</div>

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2017 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

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