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Some recent SARS-CoV-2 variants appear to have increased transmissibility than the original strain. An underlying mechanism could be the improved ability of the variants to bind receptors on target cells and infect them. In this study, we provide atomic-level insight into the binding of the receptor binding domain (RBD) of the wild-type SARS-CoV-2 spike protein and its single (N501Y), double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants to the human ACE2 receptor. Using extensive all-atom molecular dynamics simulations and advanced free energy calculations, we estimate the associated binding affinities and binding hotspots. We observe significant secondary structural changes in the RBD of the mutants, which lead to different binding affinities. We find higher binding affinities of the double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants than the wild type and the N501Y variant, which could contribute to the higher transmissibility of recent variants containing these mutations.

The present study aimed to reveal the molecular mechanism of T-2 toxin-induced cerebral edema by aquaporin-4 (AQP4) blocking and permeation. AQP4 is a class of aquaporin channels that is mainly expressed in the brain, and its structural changes lead to life-threatening complications such as cardio-respiratory arrest, nephritis, and irreversible brain damage. We employed molecular dynamics simulation, text mining, and in vitro and in vivo analysis to study the structural and functional changes induced by the T-2 toxin on AQP4. The action of the toxin leads to disrupted permeation of water and permeation coefficients are found to be affected, from the native (2.49 ± 0.02 × 10-14 cm3/s) to toxin-treated AQP4 (7.68 ± 0.15 × 10-14 cm3/s) channels. Furthermore, the T-2 toxin forms strong electrostatic interactions at the binding site and pushes the key residues (Ala210, Phe77, Arg216, and His201) outward at the selectivity filter. Also, the role of a histidine residue in the AQP4 channel was identified by alchemical transformation and umbrella sampling methods. Alchemical free-energy perturbation energy for H201A ↔ A201H, which was found to be 3.07 ± 0.18 kJ/mol, indicates the structural importance of the histidine residue at 201. In addition, histopathology and expression of AQP4 in the Mus musculus brain tissues show the damaged and altered expression of the protein. Text mining reveals the co-occurrence of genes/proteins associated with the AQP4 expression and T-2 toxin-induced cell apoptosis, which leads to cerebral edema.

A novel bis-anthracene molecule linked to bis-pyridine by xylylene dibromide (APC) was synthesized as a potent sensor for the detection of Al3+ ions. Receptor APC exhibits high affinity towards Al3+ ions through fluorescence ‘off–on’ behaviour in HEPES-buffered THF–H2O (1 : 1, (v/v) HEPES = 50 mM, pH = 7.4) solution with a detection limit of 0.89 × 10−6 M. The affinity between receptor APC and Al3+ ions can be attributed to the photoinduced electron transfer (PET) mechanism. Furthermore, the receptor APC can be employed for the detection of Al3+ ions in various effluent water samples and in microbial bioimaging.

Rapid pathogen detection and identification of its serovars are crucial to provide essential treatment during pandemic circumstances. Herein, we developed a facile and versatile FRET-based aptasensor for rapid Salmonella paratyphi A detection. The ssDNA aptamers specific towards pathogenic Salmonella paratyphi A were generated via whole-cell SELEX. The aptamer was conjugated onto quantum dot (QD) that served as the molecular beacon and graphene oxide (GO) was used as fluorescence quencher. The detection of Salmonella paratyphi A leads to the quenching of QD fluorescence due to the non-covalent interaction between GO and CdTe quantum dot. The assay shows a detection limit up to 10 cfu·mL−1 with no cross-reactivity towards closely related species. The spiking analysis demonstrated an inter-assay coefficient of variance less than 8 % and recovery rate between 85%-102% mitigates assay reliability. Further analysis with commercially available ELISA kit validated the reliability of the developed aptasensor. Furthermore, molecular dynamics simulation was used to establish the mechanism of action of generated aptamer against bacterial DNA gyrase protein. The strong non-bonded interaction energies along with hydrogen bonds between the aptamer and protein inhibit the function of the bacteria.

T-2 toxin is one of the potent mycotoxins responsible for several pathological conditions in humans and animals. This nonvolatile low molecular weight toxin compound shows strong resistance to degradation at room temperature as well as at autoclaving temperature. The inhibition of acetylcholinesterase and cytochrome P450 receptor by T-2 toxin leads to many pathological conditions as these two receptors involved in many pathways. Here, we have used melatonin as a protection agent against T-2 toxin in both receptor systems. Using molecular docking, molecular dynamics simulation and free energy calculations we have shown that melatonin can act as a potent inhibitor of T-2 toxin in acetylcholinesterase and cytochrome P450.

Numerous chemosensors have been developed for next-generation detection systems because of their ease of use and promising characteristics to distinguish signals between various analytes binding. However, given their typically poor emission response and arduous preparation methods, very few chemosensing probes have been commercialized to date. In this work, a simple, naphthoquinone-based mitochondria-targeting chemosensor (CIA) has been fabricated for the simultaneous detection of Cu2+ and GSSG (glutathione oxidized) through an “on-off” mode in a buffered semi-aqueous solution. Significantly, the CIA chemosensor showed a sensitive detection response towards Cu2+ and GSSG with low detection limits (0.309 μM, and 0.226 μM, respectively). In addition, the detection mechanism of CIA was thoroughly verified and confirmed using numerous analytical techniques. Furthermore, CIA was utilized as a sequential fluorescence biomarker to detect Cu2+ in human cervical cancer cell lines. These findings indicate that the chemosensor CIA can discriminate human cancer cells from normal cells. The CIA was also confirmed to possess the ability to target mitochondria. More importantly, the present CIA chemosensor detected Cu2+ in zebrafish larvae, indicating the probe has tissue penetration ability.

The goal of the present work was to fabricate a new low-cost, easy-to-prepare, dual-channel fluorescence chemosensor comprised of acridine-diphenylacetyl moieties (NDA) to enable remarkable Sn4+ detection in water and biological medium. The resulting NDA–Sn4+ complex was utilized for the distinguished identification of Cr2O72- ions from other anions and biomolecules. These investigations involve the absorption, fluorescence, and electrochemical methods for the detection of Sn4+ and Cr2O72- ions in pure water. The mechanism for NDA-mediated Sn4+ detection was experimentally determined by FT-IR, NMR titrations, mass (ESI) analyses, and DFT calculations. The obtained results indicate that the NDA chemosensor possessed excellent performance characteristics including good water solubility and compatibility, quick response time (less than 10 s), high sensitivity (Sn4+ = 0.268 μM and Cr2O72- = 0.160 μM), and selectivity against coexisting metals, anions, amino acids, and peptides. The chemosensor NDA induced negligible toxicity in live cells and was successfully utilized as a biomarker for the tracking of Sn4+ in human normal and cancer cells. More importantly, NDA demonstrates distinguished recognition of Sn4+ in human cancer cells rather than in normal live cells. Additionally, NDA was shown to act as a mitochondria-targeted probe in FaDu cells.

A novel coronavirus (SARS-CoV-2) has caused a major outbreak in human all over the world. There are several proteins interplay during the entry and replication of this virus in human. Here, we have used text mining and named entity recognition method to identify co-occurrence of the important COVID 19 genes/proteins in the interaction network based on the frequency of the interaction. Network analysis revealed a set of genes/proteins, highly dense genes/protein clusters and sub-networks of Angiotensin-converting enzyme 2 (ACE2), Helicase, spike (S) protein (trimeric), membrane (M) protein, envelop (E) protein, and the nucleocapsid (N) protein. The isolated proteins are screened against procyanidin-a flavonoid from plants using molecular docking. Further, molecular dynamics simulation of critical proteins such as ACE2, Mpro and spike proteins are performed to elucidate the inhibition mechanism. The strong network of hydrogen bonds and hydrophobic interactions along with van der Waals interactions inhibit receptors, which are essential to the entry and replication of the SARS-CoV-2. The binding energy which largely arises from van der Waals interactions is calculated (ACE2=-50.21 ± 6.3, Mpro=-89.50 ± 6.32 and spike=-23.06 ± 4.39) through molecular mechanics Poisson-Boltzmann surface area also confirm the affinity of procyanidin towards the critical receptors. Communicated by Ramaswamy H. Sarma, Graphical Abstract

Aquaporins form a large family of transmembrane protein channel that facilitates selective and fast water transport across the cell membrane. The inhibition of aquaporin channels leads to many water-related diseases such as nephrogenic diabetes insipidus, edema, cardiac arrest, and stroke. Herein, we report the molecular mechanism of mycotoxins (citrinin, ochratoxin-A, and T-2 mycotoxin) inhibition of aquaporin-2 (AQP2) and arginine vasopressin receptor 2. Molecular docking, molecular dynamics simulations, quantum chemical calculations, residue conservation-coupling analysis, sequence alignment, and in vivo studies were utilized to explore the binding interactions between the mycotoxins and aquaporin-2. Theoretical studies revealed that the electrostatic interactions induced by the toxins pulled the key residues (187Arg, 48Phe, 172His, and 181Cys) inward, hence reduced the pore diameter and water permeation. The permeability coefficient of the channel was reduced from native ((3.32 ± 0.75) × 10-14 cm3/s) to toxin-treated AQP2 ((1.08 ± 0.03) × 10-14 cm3/s). The hydrogen bonds interruption and formation of more hydrogen bonds with toxins also led to the reduced number of water permeation. Further, in vivo studies showed renal damages and altered level of aquaporin expression in mycotoxin-treated Mus musculus. Furthermore, the multiple sequence alignments among the model organism along with evolutionary coupling analysis provided the information about the interdependences of the residues in the channel.

Several fluorescence and colorimetric chemosensory for Sn2+ detection in an aqueous media have been reported, but applications remain limited for discriminative Sn2+ detection in live human cells and zebrafish larvae. Herein, a mitochondria-targeted Sn2+ “turn-on” colorimetric and fluorescence chemosensor, 2CTA, with an aggregation-induced emission (AIE) response was developed. The sensing of Sn2+ was enabled by a reduction-enabled binding pathway, with the conversion of –C˭O groups to –C–OH groups at the naphthoquinone moiety. The color changed from light maroon to milky white in a buffered aqueous solution. The chemosensor 2CTA possessed the excellent characteristics of good water solubility, fast response (less than 10 s), and high sensitivity (79 nM) and selectivity for Sn2+ over other metal ions, amino acids, and peptides. The proposed binding mechanism was experimentally verified by means of FT-IR and NMR studies. The chemosensor 2CTA was successfully employed to recognize Sn2+ in live human cells and in zebrafish larvae. In addition, a colocalization study proved that the chemosensor had the ability to target mitochondria and overlapped almost completely with MitoTracker Red. Furthermore, a bioimaging study of live cells demonstrated the discriminative detection of Sn2+ in human cancer cells and the practical applications of 2CTA in biological systems.

A new colorimetric and ratiometric fluorescence chemosensor 4-((3-(octadecylthio)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)benzenesulfonamide (4DBS) was synthesized and investigated for the selective detection of Hg2+ in DMSO-H2O (9:1, v/v) solution. The chemosensor was efficiently synthesized in two steps via Michael-like addition and nucleophilic substitution reactions. The ratiometric fluorescence turn-on response was obtained towards Hg2+, and its fluorescence emission peak was red-shifted by 140 nm with an associated color change from light maroon to pale yellow due to the intramolecular charge transfer effect. The formed coordination metal complex was further evaluated by FT-IR, 1H NMR, and quantum chemical analyses to confirm the binding mechanism. The detection process was sensitive/reversible, and the calculated limit of detection for Hg2+ was 0.451 µM. Furthermore, 4DBS was effectively utilized as a bioimaging agent for detection of Hg2+ in live cells and zebrafish larvae. Additionally, 4DBS showed distinguishing detection of Hg2+ in cancer cells in comparison with normal cells. Thus, 4DBS could be employed as an efficient bioimaging probe for discriminative identification of human cancer cells.

Here we demonstrate a facile and versatile fluorescence resonance energy transfer (FRET) based aptasensor for rapid detection of Salmonella paratyphi A. The assay shows a detection limit up to 10 cfu·mL−1 with no cross-reactivity with other bacterial species. Less than 8% of inter-assay coefficient variance and recovery rate between 85 and 102% attests the assay reliability. The advantages of FRET-based aptamer assay over the conventional immunoassay formats such as ELISA are the specificity, speed, reliability, and simplicity of the assay. The ssDNA aptamers specific towards pathogenic Salmonella paratyphi A were generated via whole-cell SELEX. The aptamer was conjugated onto quantum dot (QD) that served as the molecular beacon and graphene oxide (GO) was used as a fluorescence quencher. Thus the proposed method enables detection of target pathogen using FRET-based assay. Further interaction of aptamer with pathogen protein DNA gyrase was explored using classical molecular dynamics simulation.

A new chemosensor (NANH) based on naphthyl moiety was synthesized with good selectivity and sensitivity towards Al3+ ions via the inhibition by operating through dual mechanisms like photo-induced electron transfer (PET) and excited-state intramolecular proton transfer (ESIPT). The synthesized NANH was validated by various techniques such as 1H, 13C NMR and mass spectrum. While prominent fluorescent enhancement was observed from the NANH upon binding with Al3+ ions, however, other metal ions have not responded in the emission spectrum. Detection limit and association constant of NANH for Al3+ were calculated as 1.2 × 10−7 M and 4.09 × 104 M−1 by using fluorescence titration method. Binding ratio (1:1) of NANH with Al3+ ions were proved by Job's plot and DFT studies. Furthermore, aluminium in variety of water samples was determined, and NANH could be used for biosensing of Al3+ in living cells.

The structural stability and transport properties of the cyclic peptide nanotube (CPN) 8 × [Cys–Gly–Met–Gly]2 in different phospholipid bilayers such as POPA (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acid), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine) with water have been investigated using molecular dynamics (MD) simulation. The hydrogen bonds and non-bonded interaction energies were calculated to study the stability in different bilayers. One µs MD simulation in POPA lipid membrane reveals the stability of the cyclic peptide nanotube, and the simulations at various temperatures manifest the higher stability of 8 × [Cys–Gly–Met–Gly]2. We demonstrated that the presence of sulphur-containing amino acids in CPN enhances the stability through disulphide bonds between the adjacent rings. Further, the water permeation coefficient of the CPN is calculated and compared with human aquaporin-2 (AQP2) channel protein. It is found that the coefficients are highly comparable to the AQP2 channel though the mechanism of water transport is not similar to AQP 2; the flow of water in the CPN is taking place as a two-line 1–2–1–2 file fashion. In addition to that, the transport behavior of Na+ and K+ ions, single water molecule, urea and anti-cancer drug fluorouracil were investigated using pulling simulation and potential of mean force calculation. The above transport behavior shows that Na+ is trapped in CPN for a longer time than other molecules. Also, the interactions of the ions and molecules in Cα and mid-Cα plane were studied to understand the transport behavior of the CPN. AbbreviationsAQP2Aquaporin-2CPNCyclic peptide nanotubeMDMolecular dynamicsPOPA1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acidPOPE1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolaminePOPG1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerolPOPS1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine Aquaporin-2 Cyclic peptide nanotube Molecular dynamics 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acid 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine Communicated by Ramaswamy H. Sarma

The structural stability of 8 × ([D-Leu-L-Lys-(D-Gln-L-Ala)3]) cyclic peptide nanotube (CPN) in water and different phospholipid bilayers were explored by 100 ns independent molecular dynamics (MD) simulations. The role of non-bonded interaction energy between the side and main chains of cyclic peptide rings in different membrane environments assessed, wherein the repulsive electrostatic interaction energy between neighbouring cyclic peptide rings was found adequate to break hydrogen bond energy thereby to crumple CPN. Further, the water permeation across the CPN channel was studied in four types of phospholipid bilayers- DMPG (1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol), DMPS (1,2-Dimyristoyl-sn-glycero-3-phosphoserine), POPC (1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and POPE (1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine) from MD simulations. DMPS membrane shows higher non-bonded interaction energies (−1913.06 kJ/mol of electrostatic interaction energy and −994.13 kJ/mol of van der Waals interaction energy) with CPN due to the presence of polar molecules in lipid structure. Thusly, the non-bonded interaction energies were essential towards the stability of CPN than hydrogen bonds between the nearby cyclic peptides. The result also reveals the role of side chains, hydrogen bonds and non-bonded interaction energies in an aqueous environment. The diffusion coefficient of water obtained from means square deviation calculation shows similar coefficients irrespective of the lipid surroundings. However, the permeation coefficients demonstrate water flow in the channel relies upon the environment.