Simulation approaches to ion channel structure–function relationships

2001 ◽  
Vol 34 (4) ◽  
pp. 473-561 ◽  
Author(s):  
D. Peter Tieleman ◽  
Phil C. Biggin ◽  
Graham R. Smith ◽  
Mark S. P. Sansom
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ion Selectivity ◽  
Mean Field ◽  
Transport Processes ◽  
Channel Structure ◽  
Potential Profile ◽  
Model Systems ◽  
Atomistic Simulations ◽  
K Channels

1. Introduction 4751.1 Ion channels 4751.1.1 Gramicidin 4761.1.2 Helix bundle channels 4771.1.3 K channels 4801.1.4 Porins 4831.1.5 Nicotinic acetylcholine receptor 4831.1.6 Physiological properties 4831.2 Simulations 4841.2.1 Atomistic versus mean-field simulations 4842. Atomistic simulations 4852.1 Modelling of ion-interaction parameters 4852.1.1 Interatomic distances and the problem of ionic radii 4862.1.2 Solvation energy 4872.1.3 Hydration shells and coordination numbers 4892.1.4 Parameters in common use and transferability 4912.1.5 Summary 4912.2 Water in pores versus bulk 4912.2.1 Simple pore models 4942.2.2 gA 4952.2.3 Alm 4962.2.4 LS36 (and LS24) 4962.2.5 Nicotinic receptor M2δ5 4972.2.6 Influenza A M2 4972.2.7 K channels 4972.2.8 nAChR 4982.2.9 Porins 4982.2.10 Relevance 4992.2.11 Problems with simulations 5012.3 Dynamics of ions in pores 5032.3.1 Simple pore models 5032.3.2 Helix bundles 5042.3.3 gA and KcsA 5052.4 Energetics of permeation and ion selectivity 5092.4.1 Potential and free energy profiles 5092.4.2 gA 5102.4.3 α-Helix bundles 5112.4.4 KcsA 5122.4.5 Ion selectivity 5142.4.6 Problems of estimating energetic profiles 5152.5 Conformational changes 5162.5.1 gA 5162.5.2 Alm and LS3 5162.5.3 KcsA 5172.6 Protonation states 5233. Coarse-grained simulations 5243.1 Introduction 5243.1.1 Predicting conductance magnitudes 5253.2 Electro-diffusion: the Nernst–Planck approach 5263.2.1 Calculating the potential profile from Poisson and PB theory 5283.2.2 Calculating the potential profile from BD simulations 5303.2.3 Combining Nernst–Planck and Poisson: PNP 5303.3 Beyond PNP 5323.4 BD simulations 5323.4.1 Basic theory in ion channels 5323.4.2 Incorporating the environment 5333.5 Applications 5353.5.1 Model systems 5353.5.1.1 Solving the Poisson and PB equation for channel-like geometries 5353.5.1.2 Comparing PB, PNP and BD 5363.5.2 Applications to known structures 5373.5.2.1 gA 5373.5.2.2 Porin 5393.5.2.3 LS3 5403.5.2.4 Alm 5423.5.2.5 nAChR 5423.5.2.6 KcsA 5433.6 pKa calculations 5433.7 Selectivity 5443.7.1 Anion/cation selectivity 5453.7.2 Monovalent/divalent ion selectivity 5454. Problems 5464.1 Atomistic simulations 5464.1.1 Problems 5464.1.2 Parameters 5484.2 BD 5494.3 Mean-field simulations 5495. Conclusions 5505.1 Progress 5505.2 The future 5506. Acknowledgements 5517. References 551Ion channels are proteins that form ‘holes’ in membranes through which selected ions move passively down their electrochemical gradients. The ions move quickly, at (nearly) diffusion limited rates (ca. 107 ions s−1 per channel). Ion channels are central to many properties of cell membranes. Traditionally they have been the concern of neuroscientists, as they control the electrical properties of the membranes of excitable cells (neurones, muscle; Hille, 1992). However, it is evident that ion channels are present in many types of cell, not all of which are electrically excitable, from diverse organisms, including plants, bacteria and viruses (where they are involved in functions such as cell homeostasis) in addition to animals. Thus ion channels are of general cell biological importance. They are also of biomedical interest, as several dizeases (‘channelopathies’) have been described which are caused by changes in properties of a specific ion channel (Ashcroft, 2000). Moreover, passive diffusion channels for substances other than ions are common (porins, aquaporins), as are active membrane transport processes coupled to ion gradients or ATP hydrolysis. An understanding of ion channels may also provide a gateway to understanding these processes.

Ion Channels in Plants

2012 ◽  
Vol 92 (4) ◽  
pp. 1777-1811 ◽  
Author(s):  
Rainer Hedrich
Keyword(s):  
Plasma Membrane ◽  
Ion Channels ◽  
Patch Clamp ◽  
Ion Channel ◽  
Potassium Channel ◽  
Guard Cells ◽  
Channel Structure ◽  
Model Systems ◽  
Dependent Manner ◽  
Inward Rectifiers

Since the first recordings of single potassium channel activities in the plasma membrane of guard cells more than 25 years ago, patch-clamp studies discovered a variety of ion channels in all cell types and plant species under inspection. Their properties differed in a cell type- and cell membrane-dependent manner. Guard cells, for which the existence of plant potassium channels was initially documented, advanced to a versatile model system for studying plant ion channel structure, function, and physiology. Interestingly, one of the first identified potassium-channel genes encoding the Shaker-type channel KAT1 was shown to be highly expressed in guard cells. KAT1-type channels from Arabidopsis thaliana and its homologs from other species were found to encode the K+-selective inward rectifiers that had already been recorded in early patch-clamp studies with guard cells. Within the genome era, additional Arabidopsis Shaker-type channels appeared. All nine members of the Arabidopsis Shaker family are localized at the plasma membrane, where they either operate as inward rectifiers, outward rectifiers, weak voltage-dependent channels, or electrically silent, but modulatory subunits. The vacuole membrane, in contrast, harbors a set of two-pore K+ channels. Just very recently, two plant anion channel families of the SLAC/SLAH and ALMT/QUAC type were identified. SLAC1/SLAH3 and QUAC1 are expressed in guard cells and mediate Slow- and Rapid-type anion currents, respectively, that are involved in volume and turgor regulation. Anion channels in guard cells and other plant cells are key targets within often complex signaling networks. Here, the present knowledge is reviewed for the plant ion channel biology. Special emphasis is drawn to the molecular mechanisms of channel regulation, in the context of model systems and in the light of evolution.

scholarly journals CORRELATIONAL PATCH-CLAMP SPECTROMETRY OF THE ION CHANNELS

2017 ◽  
Author(s):  
Oleg Gradov
Keyword(s):  
Ion Channels ◽  
Patch Clamp ◽  
Ion Channel ◽  
Conformational Changes ◽  
Metal Ion ◽  
Ion Selectivity ◽  
Special Kind ◽  
Channel Structure ◽  
Spectral Processing ◽  
Electrophysiological Response

Membrane ion channels operate in accordance with the main principles of coordination chemistry. Coordination number is known to determine the ion selectivity of the sodium and potassium channels. there are known both ligand-dependent and ligand-controlled ion channels operating within the supramolecular coordination fixation principles. The channel-forming ionophores form the structures which bind cations via coordination bonds leading to the conformational changes with the adjustment of the whole supramolecular architecture providing the ion channel selectivity. Such kind of non-covalent systems underlie the electrogenic membrane functions and the potential-controlled transmembrane ion transfer systems. They can be studied by means of the path-clamp method (i.e. the local membrane potential fixation), such as the «anion clamp», applied together with the analysis of the metal ion coordination geometry with the ion channels. However, such methods are not capable to register the ion channel conformational state in situ - during the ion coordination - with the molecular resolution of the ion channel structure. In this regard there is a need to develop dynamical methods capable of the simultaneous registration of the conformational and metallomic / elementomic coordination parameters and the electrophysiological response to the ion coordination. We propose to develop for this purpose a special kind of spectroscopic systems providing registration of the electrophysiological parameters and the single ion channel response by means of the local potential fixation techniques (patch-clamp / voltage-clamp) with the advanced spectral processing and the subsequent data mining, with the simultaneous spectral detection of the ion channel state as a coordination and conformationally labile supramolecular structure, with the final data processing results presented not as the single spectra, but as the spectral correlogram.Градов О. В., Орехов Ф. К. Корреляционная патч-кламп-спектрометрия ионных каналов – сочетание спектрального анализа электрофизиологического отклика каналома в нежестком реальном времени и методов спектроскопии ионных каналов как координационных (комплексных) структур // Биомедицинская инженерия и электроника. — 2016. — № 2(13). — С. 5–28.

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.

Ion Channel Permeation and Selectivity

2019 ◽  
Author(s):  
Juan J. Nogueira ◽  
Ben Corry
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ion Selectivity ◽  
Ionic Currents ◽  
Biological Processes ◽  
Ion Permeation ◽  
Voltage Gated ◽  
Physical Mechanisms ◽  
Theoretical Approaches ◽  
Mechanistic Insight

Many biological processes essential for life rely on the transport of specific ions at specific times across cell membranes. Such exquisite control of ionic currents, which is regulated by protein ion channels, is fundamental for the proper functioning of the cells. It is not surprising, therefore, that the mechanism of ion permeation and selectivity in ion channels has been extensively investigated by means of experimental and theoretical approaches. These studies have provided great mechanistic insight but have also raised new questions that are still unresolved. This chapter first summarizes the main techniques that have provided significant knowledge about ion permeation and selectivity. It then discusses the physical mechanisms leading to ion permeation and the explanations that have been proposed for ion selectivity in voltage-gated potassium, sodium, and calcium channels.

Ion channels and disease

2020 ◽  
pp. 246-255
Author(s):  
Frances Ashcroft ◽  
Paolo Tammaro
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Single Channel ◽  
Cell Types ◽  
Channel Structure ◽  
Channel Proteins ◽  
Channel Function ◽  
Ion Channel Proteins ◽  
Single Channel Currents ◽  
Channel Currents

Ion channels are membrane proteins that act as gated pathways for the movement of ions across cell membranes. They are found in both surface and intracellular membranes and play essential roles in the physiology of all cell types. An ever-increasing number of human diseases are now known to be caused by defects in ion channel function. To understand how ion channel defects give rise to disease, it is helpful to understand how the ion channel proteins work. This chapter therefore considers what is known of ion channel structure, explains the properties of the single ion channel, and shows how single-channel currents give rise to action potentials and synaptic potentials.

scholarly journals Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny

2013 ◽  
Vol 2013 ◽  
pp. 1-25 ◽  
Author(s):  
Leonhard Linta ◽  
Marianne Stockmann ◽  
Qiong Lin ◽  
André Lechel ◽  
Christian Proepper ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Ion Selectivity ◽  
Expression Patterns ◽  
Stem Cell Differentiation ◽  
Human Keratinocytes ◽  
Ips Cells ◽  
Cellular Processes ◽  
Gating Mechanism ◽  
Channel Expression

Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated. Additionally, iPSCs express a much higher number of ion channels compared to keratinocytes. Further, to narrow down specificity of ion channel expression in iPS cells we compared their expression patterns with differentiated progeny, namely, neurons and cardiomyocytes derived from iPS cells. To conclude, hiPSCs exhibit a very considerable and diverse ion channel expression pattern. Their detailed analysis could give an insight into their contribution to many cellular processes and even disease mechanisms.

Regulation of ion channel structure and function by reactive oxygen-nitrogen species

2003 ◽  
Vol 285 (6) ◽  
pp. L1184-L1189 ◽  
Author(s):  
Sadis Matalon ◽  
Karin M. Hardiman ◽  
Lucky Jain ◽  
Douglas C. Eaton ◽  
Michael Kotlikoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ion Channels ◽  
Ion Channel ◽  
Posttranslational Modifications ◽  
Regulation Of Gene Expression ◽  
Reactive Oxygen ◽  
Cellular Level ◽  
Channel Structure ◽  
Nitrogen Species ◽  
Channel Proteins

Ion channels subserve diverse cellular functions. Reactive oxygen and nitrogen species modulate ion channel function by a number of mechanisms including 1) transcriptional regulation of gene expression, 2) posttranslational modifications of channel proteins, i.e. nitrosylation, nitration, and oxidation of key amino acid residues, 3) by altering the gain in other signaling pathways that may in turn lead to changes in channel activity or channel gene expression, and 4) by modulating trafficking or turnover of channel proteins, as typified by oxygen radical activation of NF-kB, with subsequent changes in proteasomal degradation of channel degradation. Regardless of the mechanism, as was discussed in a symposium at the 2003 Experimental Biology Meeting in San Diego, CA, changes in the cellular level of reactive oxygen and nitrogen species can have profound effects on the activity of ion channels and cellular function.

scholarly journals Selective activation of mechanosensitive ion channels using magnetic particles

2007 ◽  
Vol 5 (25) ◽  
pp. 855-863 ◽  
Author(s):  
Steven Hughes ◽  
Stuart McBain ◽  
Jon Dobson ◽  
Alicia J El Haj
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Magnetic Particles ◽  
Channel Structure ◽  
Biological Research ◽  
Mechanical Forces ◽  
Extracellular Loop ◽  
Whole Cell ◽  
Mechanosensitive Ion Channels ◽  
Loop Region

This study reports the preliminary development of a novel magnetic particle-based technique that permits the application of highly localized mechanical forces directly to specific regions of an ion-channel structure. We demonstrate that this approach can be used to directly and selectively activate a mechanosensitive ion channel of interest, namely TREK-1. It is shown that manipulation of particles targeted against the extended extracellular loop region of TREK-1 leads to changes in whole-cell currents consistent with changes in TREK-1 activity. Responses were absent when particles were coated with RGD (Arg–Gly–Asp) peptide or when magnetic fields were applied in the absence of magnetic particles. It is concluded that changes in whole-cell current are the result of direct force application to the extracellular loop region of TREK-1 and thus these results implicate this region of the channel structure in mechano-gating. It is hypothesized that the extended loop region of TREK-1 may act as a tension spring that acts to regulate sensitivity to mechanical forces, in a nature similar to that described for MscL. The development of a technique that permits the direct manipulation of mechanosensitive ion channels in real time without the need for pharmacological drugs has huge potential benefits not only for basic biological research of ion-channel gating mechanisms, but also potentially as a tool for the treatment of human diseases caused by ion-channel dysfunction.

Composite Synthetic Membranes Containing Native and Engineered Transport Proteins

2008 ◽  
Author(s):  
John Cuppoletti
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Membrane Transport ◽  
Composite Membranes ◽  
Transport Proteins ◽  
Transport Processes ◽  
Stable Form ◽  
Ion Pumps ◽  
Biological Transport ◽  
Ion Gradients

Our membrane transport protein laboratory has worked with material scientists, computational chemists and electrical and mechanical engineers to design bioactuators and sensing devices. The group has demonstrated that it is possible to produce materials composed native and engineered biological transport proteins in a variety of synthetic porous and solid materials. Biological transport proteins found in nature include pumps, which use energy to produce gradients of solutes, ion channels, which dissipate ion gradients, and a variety of carriers which can either transport substances down gradients or couple the uphill movement of substances to the dissipation of gradients. More than one type of protein can be reconstituted into the membranes to allow coupling of processes such as forming concentration gradients with ion pumps and dissipating them with an ion channel. Similarly, ion pumps can provide ion gradients to allow the co-transport of another substance. These systems are relevant to bioactuation. An example of a bioactuator that has recently been developed in the laboratory was based on a sucrose-proton exchanger coupled to a proton pump driven by ATP. When coupled together, the net reaction across the synthetic membrane was ATP driven sucrose transport across a flexible membrane across a closed space. As sucrose was transported, net flow of water occurred, causing pressure and deformation of the membrane. Transporters are regulated in nature. These proteins are sensitive to voltage, pH, sensitivity to a large variety of ligands and they can be modified to gain or lose these responses. Examples of sensors include ligand gated ion channels reconstituted on solid and permeable supports. Such sensors have value as high throughput screening devices for drug screening. Other sensors that have been developed in the laboratory include sensors for membrane active bacterial products such as the anthrax pore protein. These materials can be self assembled or manufactured by simple techniques, allowing the components to be stored in a stable form for years before (self) assembly on demand. The components can be modified at the atomic level, and are composed of nanostructures. Ranges of sizes of structures using these components range from the microscopic to macroscopic scale. The transport proteins can be obtained from natural sources or can be produced by recombinant methods from the genomes of all kingdoms including archea, bacteria and eukaryotes. For example, the laboratory is currently studying an ion channel from a thermophile from deep sea vents which has a growth optimum of 90 degrees centigrade, and has membrane transport proteins with very high temperature stability. The transport proteins can also be genetically modified to produce new properties such as activation by different ligands or transport of new substances such as therapeutic agents. The structures of many of these proteins are known, allowing computational chemists to help understand and predict the transport processes and to guide the engineering of new properties for the transport proteins and the composite membranes. Supported by DARPA and USARMY MURI Award and AFOSR.

scholarly journals Applications of Distributed-Order Fractional Operators: A Review

Entropy ◽  
2021 ◽  
Vol 23 (1) ◽  
pp. 110
Author(s):  
Wei Ding ◽  
Sansit Patnaik ◽  
Sai Sidhardh ◽  
Fabio Semperlotti
Keyword(s):  
Fractional Calculus ◽  
Real World ◽  
Transport Processes ◽  
Model Systems ◽  
Variable Order ◽  
Fractional Operators ◽  
Research Activity ◽  
Road Map ◽  
Real World Applications ◽  
Distributed Order

Distributed-order fractional calculus (DOFC) is a rapidly emerging branch of the broader area of fractional calculus that has important and far-reaching applications for the modeling of complex systems. DOFC generalizes the intrinsic multiscale nature of constant and variable-order fractional operators opening significant opportunities to model systems whose behavior stems from the complex interplay and superposition of nonlocal and memory effects occurring over a multitude of scales. In recent years, a significant amount of studies focusing on mathematical aspects and real-world applications of DOFC have been produced. However, a systematic review of the available literature and of the state-of-the-art of DOFC as it pertains, specifically, to real-world applications is still lacking. This review article is intended to provide the reader a road map to understand the early development of DOFC and the progressive evolution and application to the modeling of complex real-world problems. The review starts by offering a brief introduction to the mathematics of DOFC, including analytical and numerical methods, and it continues providing an extensive overview of the applications of DOFC to fields like viscoelasticity, transport processes, and control theory that have seen most of the research activity to date.

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