scholarly journals Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels

2016 ◽  
pp. 251-268 ◽  
Author(s):  
Hyunbum Jang ◽  
Fernando Teran Arce ◽  
Joon Lee ◽  
Alan L. Gillman ◽  
Srinivasan Ramachandran ◽  
...  
Keyword(s):  
Ion Channels ◽  
Computational Methods ◽  
Functional Studies

scholarly journals Computational Ion Channel Research: from the Application of Artificial Intelligence to Molecular Dynamics Simulations.

2020 ◽  
Vol 55 (S3) ◽  
pp. 14-45
Keyword(s):  
Artificial Intelligence ◽  
Molecular Dynamics ◽  
Ion Channels ◽  
Ion Channel ◽  
Computational Methods ◽  
Homology Modelling ◽  
Channel Structure ◽  
Learning Approaches ◽  
Qsar Analysis ◽  
Wide Range

Although ion channels are crucial in many physiological processes and constitute an important class of drug targets, much is still unclear about their function and possible malfunctions that lead to diseases. In recent years, computational methods have evolved into important and invaluable approaches for studying ion channels and their functions. This is mainly due to their demanding mechanism of action where a static picture of an ion channel structure is often insufficient to fully understand the underlying mechanism. Therefore, the use of computational methods is as important as chemical-biological based experimental methods for a better understanding of ion channels. This review provides an overview on a variety of computational methods and software specific to the field of ion-channels. Artificial intelligence (or more precisely machine learning) approaches are applied for the sequence-based prediction of ion channel family, or topology of the transmembrane region. In case sufficient data on ion channel modulators is available, these methods can also be applied for quantitative structureactivity relationship (QSAR) analysis. Molecular dynamics (MD) simulations combined with computational molecular design methods such as docking can be used for analysing the function of ion channels including ion conductance, different conformational states, binding sites and ligand interactions, and the influence of mutations on their function. In the absence of a three-dimensional protein structure, homology modelling can be applied to create a model of your ion channel structure of interest. Besides highlighting a wide range of successful applications, we will also provide a basic introduction to the most important computational methods and discuss best practices to get a rough idea of possible applications and risks.

scholarly journals Atomistic Insights of Calmodulin Gating of Complete Ion Channels

2020 ◽  
Vol 21 (4) ◽  
pp. 1285 ◽  
Author(s):  
Eider Núñez ◽  
Arantza Muguruza-Montero ◽  
Alvaro Villarroel
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Therapeutic Potential ◽  
Structural Information ◽  
Lipid Binding ◽  
Channel Structure ◽  
Extracellular Medium ◽  
Alpha Helices ◽  
Functional Studies ◽  
Direct Binding

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

CLC-0 and CFTR: Chloride Channels Evolved From Transporters

2008 ◽  
Vol 88 (2) ◽  
pp. 351-387 ◽  
Author(s):  
Tsung-Yu Chen ◽  
Tzyh-Chang Hwang
Keyword(s):  
Ion Channels ◽  
Membrane Transport ◽  
Chloride Channels ◽  
Transport Proteins ◽  
Transmembrane Conductance Regulator ◽  
Protein Families ◽  
Transmembrane Conductance ◽  
Functional Studies ◽  
Membrane Transport Proteins ◽  
Cystic Fibrosis Transmembrane

CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels play important roles in Cl− transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl− channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.

scholarly journals Chemical activation of the mechanotransduction channel Piezo1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ruhma Syeda ◽  
Jie Xu ◽  
Adrienne E Dubin ◽  
Bertrand Coste ◽  
Jayanti Mathur ◽  
...  
Keyword(s):  
Ion Channels ◽  
Lipid Bilayers ◽  
Chemical Activation ◽  
Pressure Sensors ◽  
Inactivation Kinetics ◽  
Mechanical Stimuli ◽  
Functional Studies ◽  
A Cell ◽  
And Function ◽  
Cellular Components

Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ∼3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.

Functional Studies of Synthetic Gramicidin Hybrid Ion Channels in CHO Cells

ChemBioChem ◽  
2007 ◽  
Vol 8 (5) ◽  
pp. 513-520 ◽  
Author(s):  
Ryszard Wesolowski ◽  
Anna Sommer ◽  
Hans-Dieter Arndt ◽  
Ulrich Koert ◽  
Philipp Reiß ◽  
...  
Keyword(s):  
Ion Channels ◽  
Cho Cells ◽  
Functional Studies

scholarly journals Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Koromina ◽  
Miles Flitton ◽  
Alix Blockley ◽  
Ian R. Mellor ◽  
Helen M. Knight
Keyword(s):  
Intellectual Disability ◽  
Ion Channels ◽  
Autism Spectrum ◽  
Decay Rates ◽  
Kainate Receptors ◽  
Sequencing Data ◽  
Missense Variants ◽  
Functional Studies ◽  
Neurodevelopmental Disease ◽  
Functional Variants

AbstractSchizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

scholarly journals Computational Methods of Studying the Binding of Toxins From Venomous Animals to Biological Ion Channels: Theory and Applications

2013 ◽  
Vol 93 (2) ◽  
pp. 767-802 ◽  
Author(s):  
Dan Gordon ◽  
Rong Chen ◽  
Shin-Ho Chung
Keyword(s):  
Ion Channels ◽  
Computational Modeling ◽  
Ion Channel ◽  
Computational Methods ◽  
Structural Information ◽  
Structural Features ◽  
New Drugs ◽  
Computational Techniques ◽  
Theoretical Understanding ◽  
Theoretical Concepts

The discovery of new drugs that selectively block or modulate ion channels has great potential to provide new treatments for a host of conditions. One promising avenue revolves around modifying or mimicking certain naturally occurring ion channel modulator toxins. This strategy appears to offer the prospect of designing drugs that are both potent and specific. The use of computational modeling is crucial to this endeavor, as it has the potential to provide lower cost alternatives for exploring the effects of new compounds on ion channels. In addition, computational modeling can provide structural information and theoretical understanding that is not easily derivable from experimental results. In this review, we look at the theory and computational methods that are applicable to the study of ion channel modulators. The first section provides an introduction to various theoretical concepts, including force-fields and the statistical mechanics of binding. We then look at various computational techniques available to the researcher, including molecular dynamics, Brownian dynamics, and molecular docking systems. The latter section of the review explores applications of these techniques, concentrating on pore blocker and gating modifier toxins of potassium and sodium channels. After first discussing the structural features of these channels, and their modes of block, we provide an in-depth review of past computational work that has been carried out. Finally, we discuss prospects for future developments in the field.

scholarly journals Peptide models for membrane channels

1996 ◽  
Vol 315 (2) ◽  
pp. 345-361 ◽  
Author(s):  
Derek MARSH
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Lipid Bilayer Membranes ◽  
Transmembrane Peptides ◽  
Functional Studies ◽  
Critical Issues ◽  
Peptide Models ◽  
Ion Channel Proteins ◽  
Voltage Gated Ion Channels ◽  
Pore Lining

Peptides may be synthesized with sequences corresponding to putative transmembrane domains and/or pore-lining regions that are deduced from the primary structures of ion channel proteins. These can then be incorporated into lipid bilayer membranes for structural and functional studies. In addition to the ability to invoke ion channel activity, critical issues are the secondary structures adopted and the mode of assembly of these short transmembrane peptides in the reconstituted systems. The present review concentrates on results obtained with peptides from ligand-gated and voltage-gated ion channels, as well as proton-conducting channels. These are considered within the context of current molecular models and the limited data available on the structure of native ion channels and natural channel-forming peptides.

Sign in / Sign up

Export Citation Format

Share Document