Search

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.

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.

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.

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.