Delineating residues for haemolytic activities of snake venom cardiotoxin 1 from Naja naja as probed by molecular dynamics simulations and in vitro validations

Gorai, Biswajit; Sivaraman, Thirunavukkarasu

doi:10.1016/j.ijbiomac.2016.10.091

Cited by 10 publications

(14 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The third lipid-binding protein locus was predicted and named site M. It is partly composed of the side chains of Lys residues (5,12,35), which function as centers of attraction, trapping oppositely charged lipid phosphate groups. In addition, it encompasses a number of residues located on the convex side of the CT2 molecule: L6:NH, Y22:OH, and C38:NH.…”

Section: ■ Resultsmentioning

confidence: 99%

“…However, in such calculations, the molecular details of the binding mechanism often either escape analysis or undergo substantial distortion attributed to the use of enhancing algorithms. Apart from this, the results of all-atom MD simulations of the CT/membrane interaction are not unambiguous. , This may be due to the insufficient duration of trajectories, usually only as long as 10 –7 ÷ 10 –6 s.…”

Section: Introductionmentioning

confidence: 98%

“…Despite their small size and structural stability, CT molecules currently are still poorly studied by MD. To date, only a few MD simulations of CTs binding to lipid bilayers have been reported. ,,− Most of them used algorithms accelerating the insertion process, such as CG MD, , steered MD, or a combination of several such techniques. , CG MD , simulations, as well as the evaluation of the binding energy using implicit solvent models (e.g., Monte Carlo (MC)), are able to successfully predict the equilibrium geometry of protein insertion into the membrane and have shown good consistency with experimental data. However, in such calculations, the molecular details of the binding mechanism often either escape analysis or undergo substantial distortion attributed to the use of enhancing algorithms.…”

Section: Introductionmentioning

confidence: 99%

“…Apart from this, the results of all-atom MD simulations of the CT/membrane interaction are not unambiguous. 34,35 This may be due to the insufficient duration of trajectories, usually only as long as 10 −7 ÷ 10 −6 s.…”

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Stepwise Insertion of Cobra Cardiotoxin CT2 into a Lipid Bilayer Occurs as an Interplay of Protein and Membrane “Dynamic Molecular Portraits”

Konshina

Dubovskii

Efremov

2020

J. Chem. Inf. Model.

View full text Add to dashboard Cite

For many peripheral membrane-binding polypeptides(MBPs), especially βstructural ones, the precise molecular mechanisms of membrane insertion remain unclear. In most cases, only the terminal water-soluble and membrane-bound states have been elucidated, whereas potential functionally important intermediate stages are still not understood in sufficient detail. In this study, we present one of the first successful attempts to describe step-by-step embedding of the MBP cardiotoxin 2 (CT2) from cobra Naja oxiana venom into a lipid bilayer at the atomistic level. CT2 possesses a highly conservative and rigid β-structured three-finger fold shared by many other exogenous and endogenous proteins performing a wide variety of functions. The incorporation of CT2 into the lipid bilayer was analyzed via a 2 μs all-atom molecular dynamics (MD) simulation without restraints. This process was shown to occur over a number of distinct steps, while the geometry of initial membrane attachment drastically differs from that of the final equilibrated state. In the latter one, the hydrophobic platform ("bottom") formed by the tips of the three loops is deeply buried into the lipid bilayer. This agrees well with the NMR data obtained earlier for CT2 in detergent micelles. However, the bottom is too bulky to insert itself into the membrane at once. Instead, the gradual immersion of CT2 initiated by the loop-1 was observed. This initial binding stage was also demonstrated in a series of MD runs with varying starting orientations of the toxin with respect to the bilayer surface. Apart from the nonspecific long-range electrostatic attraction and hydrophobic match/mismatch factor, several specific lipid-binding sites were identified in CT2. They were shown to promote membrane insertion by engaging in strong interactions with lipid head groups, fine-tuning the toxin−membrane accommodation. We therefore propose that the toxin insertion relies on the interplay of nonspecific and specific interactions, which are determined by the "dynamic molecular portraits" of the two players, the protein and the membrane. The proposed model does not require protein oligomerization for membrane insertion and can be further employed to design MBPs with predetermined properties with regard to particular membrane targets.

show abstract

Section: ■ Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stepwise Insertion of Cobra Cardiotoxin CT2 into a Lipid Bilayer Occurs as an Interplay of Protein and Membrane “Dynamic Molecular Portraits”

Konshina

Dubovskii

Efremov

2020

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…Different metabolomics approaches are also used to analyze low-molecular-weight components of animal venoms [ 204 ]. In addition to these experimental approaches, bioinformatics and molecular modeling studies provide guidance for rational drug design, in understanding the complex formation of venom peptides and their receptors, and in delineating novel functions of venom peptides [ 205 , 206 ].…”

Section: Methodsmentioning

confidence: 99%

Snake Venom Peptides: Tools of Biodiscovery

Munawar

Ali

Akrem

et al. 2018

Toxins

114

View full text Add to dashboard Cite

Nature endowed snakes with a lethal secretion known as venom, which has been fine-tuned over millions of years of evolution. Snakes utilize venom to subdue their prey and to survive in their natural habitat. Venom is known to be a very poisonous mixture, consisting of a variety of molecules, such as carbohydrates, nucleosides, amino acids, lipids, proteins and peptides. Proteins and peptides are the major constituents of the dry weight of snake venoms and are of main interest for scientific investigations as well as for various pharmacological applications. Snake venoms contain enzymatic and non-enzymatic proteins and peptides, which are grouped into different families based on their structure and function. Members of a single family display significant similarities in their primary, secondary and tertiary structures, but in many cases have distinct pharmacological functions and different bioactivities. The functional specificity of peptides belonging to the same family can be attributed to subtle variations in their amino acid sequences. Currently, complementary tools and techniques are utilized to isolate and characterize the peptides, and study their potential applications as molecular probes, and possible templates for drug discovery and design investigations.

show abstract

Broad‐Spectrum Detoxification of Snake Venoms With Supramolecular Materials Integrated via Molecular Recognition and Coassembly

Chen,

Tian,

Cheng

et al. 2024

Adv Healthcare Materials

View full text Add to dashboard Cite

Snakebite is a medical emergency that often leads to high mortality and morbidity in tropical and subtropical regions. The diversity in venom composition between various types of snakes necessitates the use of different specific antivenom treatments, which presents clinical and financial challenges in the management of snakebites. Therefore, developing a broad‐spectrum antidote to neutralize complex and diverse snake venoms has assumed critical importance. Herein, a broad‐spectrum antidote is developed through molecular recognition and coassembly to neutralize four kinds of snake venom toxins, those are three‐finger toxin (3FTx), snake venom metalloproteinase (SVMP), phospholipase A2 (PLA2), and snake venom serine protease (SVSP), which have high abundance and toxicity. The coassembly of sulfonate‐modified amphiphilic calixarene (SCA) and amphiphilic cyclodextrin (CD) is employed to neutralize the toxicity of 3FTx, 1,2‐dodecanedithiol (DDT) and thioetheramide phosphorylcholine (TEAPC) are introduced through coassembly to neutralize toxicity of SVMP and PLA2, respectively, and the nafamostat (NT), which can be loaded through the host‐guest complexation, is employed to neutralize toxicity of SVSP. The broad‐spectrum antidote, NT@SCA/CD/DDT/TEAPC, effectively neutralizes key toxins from the most medically important cobra and vipers, significantly improving survival rates of poisoned mice. This study conceptually validated the feasibility of broad‐spectrum detoxification and also offers a conveniently integrated supramolecular strategy.

show abstract

Delineating residues for haemolytic activities of snake venom cardiotoxin 1 from Naja naja as probed by molecular dynamics simulations and in vitro validations

Cited by 10 publications

References 100 publications

Stepwise Insertion of Cobra Cardiotoxin CT2 into a Lipid Bilayer Occurs as an Interplay of Protein and Membrane “Dynamic Molecular Portraits”

Stepwise Insertion of Cobra Cardiotoxin CT2 into a Lipid Bilayer Occurs as an Interplay of Protein and Membrane “Dynamic Molecular Portraits”

Snake Venom Peptides: Tools of Biodiscovery

Broad‐Spectrum Detoxification of Snake Venoms With Supramolecular Materials Integrated via Molecular Recognition and Coassembly

Contact Info

Product

Resources

About