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

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.

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Artificial Intelligence, Machine Learning and Deep Learning in Ion Channel Bioinformatics

Membranes ◽

10.3390/membranes11090672 ◽

2021 ◽

Vol 11 (9) ◽

pp. 672

Author(s):

Md. Ashrafuzzaman

Keyword(s):

Artificial Intelligence ◽

Machine Learning ◽

Deep Learning ◽

Ion Channels ◽

Ion Channel ◽

Research Trend ◽

Cellular Processes ◽

Research Areas ◽

Huge Data ◽

Functional Aspects

Ion channels are linked to important cellular processes. For more than half a century, we have been learning various structural and functional aspects of ion channels using biological, physiological, biochemical, and biophysical principles and techniques. In recent days, bioinformaticians and biophysicists having the necessary expertise and interests in computer science techniques including versatile algorithms have started covering a multitude of physiological aspects including especially evolution, mutations, and genomics of functional channels and channel subunits. In these focused research areas, the use of artificial intelligence (AI), machine learning (ML), and deep learning (DL) algorithms and associated models have been found very popular. With the help of available articles and information, this review provide an introduction to this novel research trend. Ion channel understanding is usually made considering the structural and functional perspectives, gating mechanisms, transport properties, channel protein mutations, etc. Focused research on ion channels and related findings over many decades accumulated huge data which may be utilized in a specialized scientific manner to fast conclude pinpointed aspects of channels. AI, ML, and DL techniques and models may appear as helping tools. This review aims at explaining the ways we may use the bioinformatics techniques and thus draw a few lines across the avenue to let the ion channel features appear clearer.

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Ion channels and disease

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0032 ◽

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.

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

Physiological Reviews ◽

10.1152/physrev.00035.2012 ◽

2013 ◽

Vol 93 (2) ◽

pp. 767-802 ◽

Cited By ~ 36

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.

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Unification and extensive diversification of M/ORF3-related ion channel proteins in coronaviruses and other nidoviruses

Virus Evolution ◽

10.1093/ve/veab014 ◽

2021 ◽

Author(s):

Yongjun Tan ◽

Theresa Schneider ◽

Prakash K Shukla ◽

Mahesh B Chandrasekharan ◽

L Aravind ◽

...

Keyword(s):

Ion Channels ◽

Ion Channel ◽

M Protein ◽

Detection Methods ◽

Homology Detection ◽

Virion Assembly ◽

Wide Range ◽

M Proteins ◽

Slow Evolution ◽

Membrane Budding

Abstract The coronavirus, SARS-CoV-2, responsible for the ongoing COVID-19 pandemic, has emphasized the need for a better understanding of the evolution of virus-host interactions. ORF3a in both SARS-CoV-1 and SARS-CoV-2 are ion channels (viroporins) implicated in virion assembly and membrane budding. Using sensitive profile-based homology detection methods, we unify the SARS-CoV ORF3a family with several families of viral proteins, including ORF5 from MERS-CoVs, proteins from beta-CoVs (ORF3c), alpha-CoVs (ORF3b), most importantly, the Matrix (M) proteins from CoVs, and more distant homologs from other nidoviruses. We present computational evidence that these viral families might utilize specific conserved polar residues to constitute an aqueous pore within the membrane-spanning region. We reconstruct an evolutionary history of these families and objectively establish the common origin of the M proteins of CoVs and Toroviruses. We also show that the divergent ORF3 clade (ORF3a/ORF3b/ORF3c/ORF5 families) represents a duplication stemming from the M protein in alpha- and beta-CoVs. By phyletic profiling of major structural components of primary nidoviruses, we present a hypothesis for their role in virion assembly of CoVs, ToroVs and Arteriviruses. The unification of diverse M/ORF3 ion channel families in a wide range of nidoviruses, especially the typical M protein in CoVs, reveal a conserved, previously under-appreciated role of ion channels in virion assembly and membrane budding. We show that M and ORF3 are under different evolutionary pressures; in contrast to the slow evolution of M as core structural component, the ORF3 clade is under selection for diversification, which suggests it might act at the interface with host molecules and/or immune attack.

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Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

10.1101/166272 ◽

2017 ◽

Author(s):

Laura-Nadine Schuhmacher ◽

Gerard Callejo ◽

Shyam Srivats ◽

Ewan St. John Smith

Keyword(s):

Carbon Dioxide ◽

Ion Channels ◽

Ion Channel ◽

Drg Neurons ◽

Whole Cell Patch Clamp ◽

Mole Rat ◽

Wide Range ◽

Naked Mole Rat ◽

Patch Clamp Electrophysiology ◽

Carbon Dioxide Levels

ABSTRACTAcid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia and carbon dioxide. Here we cloned naked mole-rat ASIC3 (nmrASIC3) and used a cell surface biotinylation assay to demonstrate that it traffics to the plasma membrane, but using whole-cell patch-clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-Guanidine-4-methylquinazoline (GMQ). However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the naked mole-rat to living in an environment with high-carbon dioxide levels.

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Unification of the M/ORF3-related proteins points to a diversified role for ion conductance in pathogenesis of coronaviruses and other nidoviruses

10.1101/2020.11.10.377366 ◽

2020 ◽

Author(s):

Yongjun Tan ◽

Theresa Schneider ◽

Prakash K. Shukla ◽

Mahesh B. Chandrasekharan ◽

L Aravind ◽

...

Keyword(s):

Ion Channels ◽

Ion Channel ◽

M Protein ◽

Homology Detection ◽

Virion Assembly ◽

Host Molecules ◽

Wide Range ◽

M Proteins ◽

Immune Attack ◽

Selection For

ABSTRACTThe new coronavirus, SARS-CoV-2, responsible for the COVID-19 pandemic has emphasized the need for a better understanding of the evolution of virus-host conflicts. ORF3a in both SARS-CoV-1 and SARS-CoV-2 are ion channels (viroporins) and involved in virion assembly and membrane budding. Using sensitive profile-based homology detection methods, we unify the SARS-CoV ORF3a family with several families of viral proteins, including ORF5 from MERS-CoVs, proteins from beta-CoVs (ORF3c), alpha-CoVs (ORF3b), most importantly, the Matrix (M) proteins from CoVs, and more distant homologs from other nidoviruses. By sequence analysis and structural modeling, we show that these viral families utilize specific conserved polar residues to constitute an ion-conducting pore in the membrane. We reconstruct the evolutionary history of these families, objectively establish the common origin of the M proteins of CoVs and Toroviruses. We show that the divergent ORF3a/ORF3b/ORF5 families represent a duplication stemming from the M protein in alpha- and beta-CoVs. By phyletic profiling of major structural components of primary nidoviruses, we present a model for their role in virion assembly of CoVs, ToroVs and Arteriviruses. The unification of diverse M/ORF3 ion channel families in a wide range of nidoviruses, especially the typical M protein in CoVs, reveal a conserved, previously under-appreciated role of ion channels in virion assembly, membrane fusion and budding. We show that the M and ORF3 are under differential evolutionary pressures; in contrast to the slow evolution of M as core structural component, the CoV-ORF3 clade is under selection for diversification, which indicates it is likely at the interface with host molecules and/or immune attack.IMPORTANCECoronaviruses (CoVs) have become a major threat to human welfare as the causative agents of several severe infectious diseases, namely Severe Acute Respiratory Syndrome (SARS), Middle Eastern Respiratory Syndrome (MERS), and the recently emerging human coronavirus disease 2019 (COVID-19). The rapid spread, severity of these diseases, as well as the potential re-emergence of other CoV-associated diseases have imposed a strong need for a thorough understanding of function and evolution of these CoVs. By utilizing robust domain-centric computational strategies, we have established homologous relationships between many divergent families of CoV proteins, including SARS-CoV/SARS-CoV-2 ORF3a, MERS-CoV ORF5, proteins from both beta-CoVs (ORF3c) and alpha-CoVs (ORF3b), the typical CoV Matrix proteins, and many distant homologs from other nidoviruses. We present evidence that they are active ion channel proteins, and the Cov-specific ORF3 clade proteins are under selection for rapid diversification, suggesting they might have been involved in interfering host molecules and/or immune attack.

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Ion Channels in Plants

Physiological Reviews ◽

10.1152/physrev.00038.2011 ◽

2012 ◽

Vol 92 (4) ◽

pp. 1777-1811 ◽

Cited By ~ 226

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.

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Molecular dynamics: a powerful tool for studying the medicinal chemistry of ion channel modulators

RSC Medicinal Chemistry ◽

10.1039/d1md00140j ◽

2021 ◽

Author(s):

Daniel Șterbuleac

Keyword(s):

Molecular Dynamics ◽

Ion Channels ◽

Ion Channel ◽

Medicinal Chemistry ◽

Transmembrane Proteins ◽

Md Simulations ◽

Biological Macromolecules ◽

Biological Targets ◽

Ion Channel Modulators

Molecular dynamics (MD) simulations allow researchers to investigate the behavior of desired biological targets at ever-decreasing costs with ever-increasing precision. Among the biological macromolecules, ion channels are remarkable transmembrane proteins,...

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00281.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. L1184-L1189 ◽

Cited By ~ 63

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.

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Briefing in Application of Machine Learning Methods in Ion Channel Prediction

The Scientific World JOURNAL ◽

10.1155/2015/945927 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Hao Lin ◽

Wei Chen

Keyword(s):

Machine Learning ◽

Ion Channels ◽

Ion Channel ◽

Inorganic Ions ◽

Correct Identification ◽

Biological Processes ◽

Learning Methods ◽

Channel Prediction ◽

Machine Learning Methods ◽

Wide Range

In cells, ion channels are one of the most important classes of membrane proteins which allow inorganic ions to move across the membrane. A wide range of biological processes are involved and regulated by the opening and closing of ion channels. Ion channels can be classified into numerous classes and different types of ion channels exhibit different functions. Thus, the correct identification of ion channels and their types using computational methods will provide in-depth insights into their function in various biological processes. In this review, we will briefly introduce and discuss the recent progress in ion channel prediction using machine learning methods.

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