Identification of the mutated sites present in the transmembrane regions of SCN1A_HUMAN (Sodium Voltage-Gated Channel Alpha Subunit 1) using Insilico techniques

2020 ◽  
Vol 5 (1) ◽  
pp. 1-6
Author(s):  
Balaji Munivelan
Keyword(s):  
Amino Acids ◽  
Outer Membrane ◽  
Structure Prediction ◽  
Homology Modelling ◽  
Transmembrane Helix ◽  
3D Structure ◽  
Docking Studies ◽  
Alpha Subunit ◽  
Voltage Gated ◽  
Gated Channel

Mutations in numerous genes which encode for voltage-gated sodium channels give rise to various epilepsy syndromes in humans. Our research investigation mainly focuses on the identification of the integral membrane protein of the SCN1A (Sodium Voltage-Gated Channel Alpha Subunit 1) in humans. Secondary, we focus on the transmembrane membrane (TP) amino acids directly involved in the epilepsy-involved mutated regions. Using Insilico protocols, we identify the TP proteins and amino acids and elucidate the Transmembrane Helix and the inside and outside amino acids regions of the SCN1A. With the help of Insilico proteomics server, the amino acids in the mutated regions involved in the TP were identified. Finally, 3D structure prediction was performed using homology modelling server and the modelled structure was cross validated for the TP and validated. The identified results were validated using molecular visualization tools. We prove that the mutated amino acids are present in the outer membrane of the TP regions. Thus, the outer membrane of sodium channel and the amino acids present in the outer membrane (T875M, R859C, and R1648H) play a vital role in Structure-Based Drug Designing and Drug Docking studies.

scholarly journals Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

2019 ◽  
Vol 13 ◽  
pp. 117793221986553 ◽  
Author(s):  
Gbolahan O Oduselu ◽  
Olayinka O Ajani ◽  
Yvonne U Ajamma ◽  
Benedikt Brors ◽  
Ezekiel Adebiyi
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
In Silico ◽  
Homology Modelling ◽  
3D Structure ◽  
Docking Studies ◽  
Binding Energies ◽  
Benzimidazole Derivatives ◽  
Adenylosuccinate Lyase ◽  
In Silico Admet

Plasmodium falciparum adenylosuccinate lyase ( PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[ d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from −6.85 to −8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

scholarly journals Genetic epilepsy with febrile seizures plus – an overview

2021 ◽  
Vol 20 (1) ◽  
pp. 21-27
Author(s):  
Madalina Radu ◽  
◽  
Eugenia Roza ◽  
Daniel Mihai Teleanu ◽  
Raluca Ioana Teleanu ◽  
...  
Keyword(s):  
Febrile Seizure ◽  
De Novo ◽  
Febrile Seizures ◽  
Alpha Subunit ◽  
Gamma Aminobutyric Acid ◽  
Voltage Gated ◽  
Genetic Epilepsy ◽  
Generalized Seizures ◽  
Gated Channel ◽  
Febrile Seizures Plus

Genetic epilepsy with febrile seizures plus (GEFS+) is characterized by a group of genetic epilepsies associated predominately with an autosomal dominant pattern, but also with de novo and autosomal-recessive inheritance, these last two found in a small number of cases. It was believed that GEFS+ is associated only with generalized seizures, but now the term “genetic epilepsy” is preferred because it has been demonstrated that GEFS+ is associated with both generalized and focal seizures. The “GEFS+ family” was defined as a family with more than two individuals with GEFS+ phenotypes, including at least one with febrile seizure or febrile seizure plus. The GEFS+ spectrum includes febrile seizures (FS), febrile seizures plus (FS+), myoclonic seizures, myoclonic-atonic seizures, absences seizures, focal or generalized seizures. The genetic mutations responsible for inhibitor-excitatory imbalance in neurons network were found in sodium voltage-gated channel alpha subunit 1 (SCN1A), sodium voltage-gated channel beta subunit 1 (SCN1B), sodium voltage-gated channel alpha subunit 2 (SCN2A), sodium voltage-gated channel alpha subunit 9 (SCN9A), gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2), which are the main gene in GEFS+ genotype.

Molecular Cloning and Structural Insights into pectin lyase proteins from different strains of Fusarium

2020 ◽  
Vol 17 ◽  
Author(s):  
Sangeeta Yadav ◽  
Gautam Anand ◽  
Vinay K Singh ◽  
Dinesh Yadav
Keyword(s):  
Structure Prediction ◽  
Disulfide Bonds ◽  
3D Structure ◽  
Chemical Characterization ◽  
Structural Features ◽  
Docking Studies ◽  
Biochemical Properties ◽  
Pectin Lyase ◽  
Homology Search ◽  
Multiple Sequence

: Pectin lyaseis an industrially important enzymeof pectinase group that degrade pectin polymers forming 4,5-unsaturated oligogalacturonides. Several fugal pectin lyase genes predominately from Aspergillus and Penicillium genera have been reported in the literature. Five pectin lyase genes were cloned from FusariumoxysporumMTCC1755, F.monoliforme var. subglutinansMTCC2015, FusariumavneceumMTCC10572, and FusariumsolaniMTCC3004 using PCR approach. Pectin lyase genes and proteins were subjected to homology search, multiple sequence alignment, motif search, physio-chemical characterization, phylogenetic tree construction, 3D structure prediction and molecular docking. Many conserved amino acids were found at several positions in all the pectin lyase proteins. Phylogenetic analysis of these proteins alongwith other pectinases revealed two major clusters representing members of lyases and hydrolases. In-silico characterization revealed pectin lyase proteins to be highly stable owing to the presence of disulfide bonds in their structure. Molecular weight and pI of these proteins were in the range 14.4 to 25.1 kDa and 4.47-9.39 respectively. Pectin lyase proteins from different Fusariumstrains were very much similar in their structural features and biochemical properties which might be due to their similarity on the primary sequence. Docking studies revealed that electrostatic forces, vander Waal and hydrogen bonds are the major interacting forces between the ligands and the enzyme. This might be accountable for comparatively higher and better activity of pectin lyase against galacturonic acid as compared to α-D-galactopyranuronic acid, galactofuranuronicacid and galactopyranuronate. Aspartate, tyrosine and tryptophan residues in the active site of the enzyme are responsible for ligand binding.

scholarly journals The Homology Modeling and Docking Investigation of Human Cathepsin B

2020 ◽  
Vol 10 (1) ◽  
pp. 26687
Author(s):  
Afshin Khara ◽  
Ehsan Jahangirian ◽  
Hossein Tarrahimofrad
Keyword(s):  
Amino Acids ◽  
Protease Inhibitors ◽  
Cystatin C ◽  
Active Site ◽  
Cathepsin B ◽  
Antigen Processing ◽  
3D Structure ◽  
Cysteine Proteases ◽  
Docking Studies ◽  
Alternative Methods

Background: Cathepsin B comprises a group of lysosomal cysteine proteases belonging to the Papain family; it has an intracellular function in the process of protein catabolism, antigen processing in the immune response, and Alzheimer’s disease. In cancers, cathepsin B interferes with autophagy and intracellular catabolism, and breaks down extracellular matrix, decreases protease inhibitors expression, and ultimately helps to accelerate metastasis, tumor malignancy, and reduce immune resistance. Methods: In this study, the 3D structure of cathepsin B was constructed using modeler and Iterative Threading ASSEmbly Refinement (I-TASSER), based on similarity to the crystallographic model of procathepsin B (1PBH). Then, the predicted cathepsin B model was evaluated using PROCHECK and PROSA for quality and reliability. Molecular studies suggested that the amino acids cysteine 108, histidine 189, and histidine 190 form the envelope of the active site of cathepsin B. The docking studies of cathepsin B was performed with protease inhibitors cystatin C, E-64 and leupeptin. Results: The lowest binding energy was related to the cathepsin B-E-64 complex. Accordingly, it was found that E64 interacts with the amino acid cysteine 108 of the active site of cathepsin B. Leupeptin made 2 hydrogen bonds with cathepsin B, but none with the active site of cathepsin amino acids. Cystatin C established a hydrogen bond with the arginine 18 of cathepsin B and made electrostatic bonds with aspartate 148 of cathepsin B. Conclusion: Therefore, the bioinformatics and docking studies of cathepsin B with its inhibitors could be used as reliable identification, treatment, and alternative methods for selecting the inhibitors and controllers of cancer progression.

Structure of crystalline VDAC, the voltage-gated channel in the mitochondrial outer membrane

1992 ◽  
Vol 50 (1) ◽  
pp. 440-441
Author(s):  
X.W. Guo ◽  
P.R. Smith ◽  
M. Radermacher ◽  
C.A. Mannella
Keyword(s):  
Neurospora Crassa ◽  
Outer Membrane ◽  
Repeat Unit ◽  
Mitochondrial Outer Membrane ◽  
Lattice Contraction ◽  
Outer Membranes ◽  
Voltage Gated ◽  
Lateral Contraction ◽  
Gated Channel ◽  
Projection Images

The voltage-gated, mitochondrial channel, VDAC, is formed by a 31-kDa outer-membrane polypeptide. Crystalline arrays of this channel, produced by phospholipase A2 treatment of Neurospora crassa mitochondrial outer membranes, consist of groups of 6 channels repeated on a parallelogram (“oblique”) lattice (a=13.3nm, b=11.5nm, γ = 109°). These membrane crystals are polymorphic, i.e. lateral contraction is triggered by a polyanion which also decreases VDAC’s gating potential. Projection images of unstained, frozen-hydrated VDAC arrays indicate that lattice contraction is accompanied by changes in the distribution of protein away from the hexameric repeat unit.

scholarly journals patGPCR: A Multitemplate Approach for Improving 3D Structure Prediction of Transmembrane Helices of G-Protein-Coupled Receptors

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hongjie Wu ◽  
Qiang Lü ◽  
Lijun Quan ◽  
Peide Qian ◽  
Xiaoyan Xia
Keyword(s):  
G Protein ◽  
Structure Prediction ◽  
Transmembrane Helix ◽  
3D Structure ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Molecular Function ◽  
Transmembrane Helices ◽  
G Protein Coupled ◽  
Multiple Template

The structures of the seven transmembrane helices of G-protein-coupled receptors are critically involved in many aspects of these receptors, such as receptor stability, ligand docking, and molecular function. Most of the previous multitemplate approaches have built a “super” template with very little merging of aligned fragments from different templates. Here, we present a parallelized multitemplate approach, patGPCR, to predict the 3D structures of transmembrane helices of G-protein-coupled receptors. patGPCR, which employs a bundle-packing related energy function that extends on the RosettaMem energy, parallelizes eight pipelines for transmembrane helix refinement and exchanges the optimized helix structures from multiple templates. We have investigated the performance of patGPCR on a test set containing eight determined G-protein-coupled receptors. The results indicate that patGPCR improves the TM RMSD of the predicted models by 33.64% on average against a single-template method. Compared with other homology approaches, the best models for five of the eight targets built by patGPCR had a lower TM RMSD than that obtained from SWISS-MODEL; patGPCR also showed lower average TM RMSD than single-template and multiple-template MODELLER.

Successful utilisation of epidural analgesia for perioperative pain management in a child with sodium voltage-gated channel alpha subunit (SCN1A) gene mutation

2020 ◽  
Vol 13 (6) ◽  
pp. e234314
Author(s):  
Jenna H Sobey ◽  
Carrie C Menser ◽  
Srijaya K Reddy ◽  
Elisabeth M Hughes
Keyword(s):  
Pain Management ◽  
Abdominal Surgery ◽  
Gene Mutation ◽  
Alpha Subunit ◽  
Perioperative Analgesia ◽  
Voltage Gated ◽  
Clinical Presentations ◽  
Gated Channel ◽  
Perioperative Pain Management ◽  
Scn1a Gene

Sodium voltage-gated channel alpha subunit (SCN1A) gene mutation is a rare disorder with a large spectrum of clinical presentations. Little is known regarding anaesthetic and analgesic management of these patients. We present a case of a child with SCN1A gene mutation that was successfully managed with an epidural for perioperative analgesia for an abdominal surgery.

scholarly journals Molecular Insights into Human Transmembrane Protease Serine-2 (TMPS2) Inhibitors against SARS-CoV2: Homology Modelling, Molecular Dynamics, and Docking Studies

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5007
Author(s):  
Safaa M. Kishk ◽  
Rania M. Kishk ◽  
Asmaa S. A. Yassen ◽  
Mohamed S. Nafie ◽  
Nader A. Nemr ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Serine Protease ◽  
Tertiary Structure ◽  
Virus Disease ◽  
Homology Modelling ◽  
3D Structure ◽  
Md Simulations ◽  
Homology Model ◽  
Docking Studies ◽  
In Silico Studies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which caused novel corona virus disease-2019 (COVID-19) pandemic, necessitated a global demand for studies related to genes and enzymes of SARS-CoV2. SARS-CoV2 infection depends on the host cell Angiotensin-Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease-2 (TMPRSS2), where the virus uses ACE2 for entry and TMPRSS2 for S protein priming. The TMPRSS2 gene encodes a Transmembrane Protease Serine-2 protein (TMPS2) that belongs to the serine protease family. There is no crystal structure available for TMPS2, therefore, a homology model was required to establish a putative 3D structure for the enzyme. A homology model was constructed using SWISS-MODEL and evaluations were performed through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). Molecular dynamics simulations were employed to investigate the stability of the constructed model. Docking of TMPS2 inhibitors, camostat, nafamostat, gabexate, and sivelestat, using Molecular Operating Environment (MOE) software, into the constructed model was performed and the protein-ligand complexes were subjected to MD simulations and computational binding affinity calculations. These in silico studies determined the tertiary structure of TMPS2 amino acid sequence and predicted how ligands bind to the model, which is important for drug development for the prevention and treatment of COVID-19.

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