Probing Enzymatic PET Degradation: Molecular Dynamics Analysis of Cutinase Adsorption and Stability.

Understanding the mechanisms influencing poly(ethylene terephthalate) (PET) biodegradation is crucial for developing innovative strategies to accelerate the breakdown of this persistent plastic. In this study, we employed all-atom molecular dynamics simulation to investigate the adsorption process of the LCC-ICCG cutinase enzyme onto the PET surface. Our results revealed that hydrophobic, π-π, and H bond interactions, specifically involving aliphatic, aromatic, and polar uncharged amino acids, were the primary driving forces for the adsorption of the cutinase enzyme onto PET. Additionally, we observed a negligible change in the enzyme's tertiary structure during the interaction with PET (RMSD = 1.35 Å), while its secondary structures remained remarkably stable. Quantitative analysis further demonstrated that there is about a 24% decrease in the number of enzyme-water hydrogen bonds upon adsorption onto the PET surface. The significance of this study lies in unraveling the molecular intricacies of the adsorption process, providing valuable insights into the initial steps of enzymatic PET degradation.

Enhancing Multifunctionality: Optimal Properties of Iron-Oxide-Reinforced Polyvinylidene Difluoride Unveiled Through Full Atom Molecular Dynamics Simulations.

Nanocomposites made of magnetite (Fe3O4) nanoparticles (NP)s with different surface chemistry and polyvinyl difluoride (PVDF) polymer were investigated using full atom molecular dynamics (MD) simulation. NPs with hydroxyl (OH), hexanoic, and oleic acid terminations were considered in this study. The effect of each surface chemistry was investigated in terms of the mechanical properties, the distribution of the internal energy around the NP, and the chain polarization gradient from the interface to the bulk. From this investigation, we find that oleic acid termination, although the most popular, is less favorable for interfacial interaction and local polarization. The OH-terminated NP results in the best configuration for the properties investigated. The hexanoic acid-grafted NP presents a good compromise. Hydrogen bonding governs the induced response of the nanocomposites. Although the hexanoic acid grafted NP presents less hydrogen bonding than the OH-terminated case, the conformation of the hexanoic acid acts as a mobility flow inhibitor, leading to a performance comparable to that of the OH-terminated NP composite. This work led to investigating routes to make nanocomposite materials with optimized properties. These results shed light on the multiple combinations offered by nanocomposites that go beyond the conventional effects of size.

Computer Simulation of the Interaction between SARS-CoV-2 Spike Protein and the Surface of Coinage Metals.

A prominent feature of the SARS-CoV-2 virus is the presence of a large glycoprotein spike protruding from the virus envelope. The spike determines the interaction of the virus with the environment and the host. Here, we used an all-atom molecular dynamics simulation method to investigate the interaction of up- and down-conformations of the S1 subunit of the SARS-CoV-2 spike with the (100) surface of Au, Ag, and Cu. Our results revealed that the spike protein is adsorbed onto the surface of these metals, with Cu being the metal with the highest interaction with the spike. In our simulations, we considered the spike protein in both its up-conformation Sup (one receptor binding domain exposed) and down-conformation Sdown (no exposed receptor binding domain). We found that the affinity of the metals for the up-conformation was higher than their affinity for the down-conformation. The structural changes in the spike in the up-conformation were also larger than the changes in the down-conformation. Comparing the present results for metals with those obtained in our previous MD simulations of Sup with other materials (cellulose, graphite, and human skin models), we see that Au induces the highest structural change in Sup, larger than those obtained in our previous studies.

Molecular Dynamics Simulations of Adsorption of SARS-CoV-2 Spike Protein on Polystyrene Surface.

A prominent feature of coronaviruses is the presence of a large glycoprotein spike (S) protruding from the viral particle. The specific interactions of a material with S determine key aspects such as its possible role for indirect transmission or its suitability as a virucidal material. Here, we consider all-atom molecular dynamics simulations of the interaction between a polymer surface (polystyrene) and S in its up and down conformations. Polystyrene is a commonly used plastic found in electronics, toys, and many other common objects. Also, previous atomic force microscopy (AFM) experiments showed substantial adhesion of S over polystyrene, stronger than in other common materials. Our results show that the main driving forces for the adsorption of the S protein over polystyrene were hydrophobic and π-π interactions with S amino acids and glycans. The interaction was stronger for the case of S in the up conformation, which exposes one highly flexible receptor binding domain (RBD) that adjusts its conformation to interact with the polymer surface. In this case, the interaction has similar contributions from the RBD and glycans. In the case of S in the down conformation, the interaction with the polystyrene surface was weaker and it was dominated by glycans located near the RBD. We do not find significant structural changes in the conformation of S, a result which is in deep contrast to our previous results with another hydrophobic surface (graphite). Our results suggest that SARS-CoV-2 virions may adsorb strongly over plastic surfaces without significantly affecting their infectivity.

In vitro biological and in silico molecular docking and ADME studies of a substituted triazine-coordinated cadmium(II) ion: efficient cytotoxicity, apoptosis, genotoxicity, and nuclease-like activity plus binding affinity towards apoptosis-related proteins.

A cadmium(II) complex containing dppt ligand with the formula [CdCl2(dppt)2], where dppt is 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine was synthesized, elucidated and submitted to in vitro cytotoxicity studies against human breast (MCF-7), glioblastoma (U-87), and lung (A549) cancer cell lines as well as mouse embryo normal cell line (NIH/3T3), in comparison with cisplatin employing MTT assay over 24 and 48 h. The complex exhibited the highest cytotoxic effect against MCF-7 cells among the other three cell lines with IC50 values of 8.7 ± 0.5 (24 h) and 1.2 ± 0.7 µM (48 h). Significantly, flow cytometric assessment of the complex-treated MCF-7 and U-87 cells demonstrated a dose-dependent induced apoptotic cell death. The cellular morphological changes were in concord with cytotoxicity and flow cytometric results. The results of comet assay showed that the complex is able to induce DNA damage in MCF-7 cells. These observations are of importance, as sustained damage to cellular DNA could lead to apoptotic cell death. The results of DNA-binding studies indicated that the complex fits into the DNA minor groove and interacts with DNA via a partial intercalation. Moreover, the complex was able to efficiently cleave pUC19 DNA through a hydrolytic mechanism. The binding affinity between the complex and apoptosis-relevant protein targets including APAF1, Bax, Bcl-2, Cas3, Cas7, and Cas9 was evaluated through molecular docking studies. In silico virtual studies revealed the complex's strong affinity towards apoptosis-related proteins; therefore the complex can act as a potential apoptosis inducer. Physicochemical, pharmacokinetics, lipophilicity, drug-likeness, and medicinal chemistry properties of the complex were also predicted through in silico absorption, distribution, metabolism and excretion studies.

Identification of new alpha-synuclein fibrillogenesis inhibitor using in silico structure-based virtual screening.

Abnormal aggregation and accumulation of alpha-synuclein (αSN) in existing neurons is associated with Parkinson's disease (PD) as one of the age-related neurodegenerative disorders. Inhibition of αSN fibrillogenesis could be considered as a solution for PD diseases treatment. Here, virtual screening (VS) approach was used to investigate available ligands in PubChem library with structural similarity with Dihydromyricetin (DHM) (as a recently introduced suitable candidate for designing of novel antiPD drugs) against aggregation of αSN chains. Primary screening identified 314 promising molecules for αSN monomer, which were further analyzed in details by their binding energy and binding modes through molecular docking method. Evidently, the compound with PubChem ID of 100968625 displayed the lowest free binding energy with ΔG0 = -7.1 kcal.mol-1 and was selected for further analysis using molecular dynamics (MD) simulation method. Analysis of MD trajectories showed that molecules of the selected ligand interact with αSN trimer via H-bond interaction and destabilize the compact structure of αSN trimer. Further, prompt in vivo testing to validate the antiPD inhibition efficiency by this molecule can save lives.

Bioluminescent Nanoluciferase-Furimamide Complex: A Theoretical Study on Different Protonation States.

Luminescence of furimamide is 150 times brighter than oxidized luciferins in firefly and renilla luciferase. However, we do not have a clear understanding of the structure, function, and dynamic behavior of the nanoluciferase-furimamide complex. Here, for the first time, the absorption and emission properties of eight different possible light emitter forms of furimamide were investigated using the time-dependent density functional theory (TD-DFT) method in the gas phase and aqueous solution. The emission oscillator strengths in the gas phase showed that emission transition may be forbidden for some forms, and fluorescence would not occur. Besides, the charge transfer (CT) as well as the orbitals involved in the transitions were analyzed. Furthermore, molecular docking results showed that furimamide is situated inside the central cavity (ß-barrel) of nanoluciferase. Analysis of the trajectory of molecular dynamics (MD) simulations suggested a less compact structure of protein in the presence of furimamide in comparison to its apo form. The quantum mechanical/molecular mechanical (QM/MM) spectroscopic properties of one form in the binding site of nanoluciferase were investigated. The evolution of the excited states (ESs) of furimamide in the binding pocket of the protein confirmed that after photoexcitation and during the relaxation of the system, a crossing point between the first two singlet ESs exists. Thus, the initially populated S2 (a π→π* transition) becomes the first singlet excited state.

Tris-chelated complexes of nickel(II) with bipyridine derivatives: DNA binding and cleavage, BSA binding, molecular docking, and cytotoxicity.

Two nickel(II) complexes with substituted bipyridine ligand of the type [Ni(NN)3](ClO4)2, where NN is 4,4'-dimethyl-2,2'-bipyridine (dimethylbpy) (1) and 4,4'-dimethoxy-2,2'-bipyridine (dimethoxybpy) (2), have been synthesized, characterized, and their interaction with DNA and bovine serum albumin (BSA) studied by different physical methods. X-ray crystal structure of 1 shows a six-coordinate complex in a distorted octahedral geometry. DNA-binding studies of 1 and 2 reveal that both complexes sit in DNA groove and then interact with neighboring nucleotides differently; 2 undergoes a partial intercalation. This is supported by molecular-docking studies, where hydrophobic interactions are apparent between 1 and DNA as compared to hydrogen bonding, hydrophobic, and π-π interactions between 2 and DNA minor groove. Moreover, the two complexes exhibit oxidative cleavage of supercoiled plasmid DNA in the presence of hydrogen peroxide as an activator in the order of 1 > 2. In terms of interaction with BSA, the results of spectroscopic methods and molecular docking show that 1 binds with BSA only via hydrophobic contacts while 2 interacts through hydrophobic and hydrogen bonding. It has been extensively demonstrated that the nature of the methyl- and methoxy-groups in ligands is a strong determinant of the bioactivity of nickel(II) complexes. This may justify the above differences in biomolecular interactions. In addition, the in vitro cytotoxicity of the complexes on human carcinoma cells lines (MCF-7, HT-29, and U-87) has been examined by MTT assay. According to our observations, 1 and 2 display cytotoxicity activity against selected cell lines. Communicated by Ramaswamy H. Sarma.

DNA and HSA interaction of Vanadium (IV), Copper (II), and Zinc (II) complexes derived from an asymmetric bidentate Schiff-base ligand: multi spectroscopic, viscosity measurements, molecular docking, and ONIOM studies.

The interaction of three complexes [Zn(II), Cu(II), and V(IV)] derived from an asymmetric bidentate Schiff-base ligand with DNA and HSA was studied using fluorescence quenching, UV-Vis spectroscopy, viscosity measurements, and computational methods [molecular docking and our Own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM)]. The obtained results revealed that the DNA and HSA affinities for binding of the synthesized compounds follow as V(IV) > Zn(II) > Cu(II) and Zn(II) > V(IV) > Cu(II), respectively. The distance between these compounds and HSA was obtained based on the Förster's theory of non-radiative energy transfer. Furthermore, computational molecular docking was carried out to investigate the DNA- and HSA-binding pose of the compounds. Molecular docking calculations showed that H-bond, hydrophobic, and π-cation interactions have dominant role in stability of the compound-HSA complexes. ONIOM method was utilized to investigate the HSA binding of the compounds more precisely in which molecular-mechanics method (UFF) and semi-empirical method (PM6) were selected for the low layer and the high layer, respectively. The results show that the structural parameters of the compounds changed along with binding, indicating the strong interaction between the compounds with HSA and DNA. Viscosity measurements as well as computational docking data suggest that all metal complexes interact with DNA, presumably by groove-binding mechanism.

Differential roles of 3-Hydroxyflavone and 7-Hydroxyflavone against nicotine-induced oxidative stress in rat renal proximal tubule cells.

Plant flavonoids are well known as antioxidants against oxidative stress induced by exposure to external pollutants. Nicotine (NIC) is one of those agents which increases renal oxidative stress, an important factor in the pathogenesis of renal epithelial injury in smokers. Although several studies had been conducted on flavonoids and oxidative stress, the mechanism of the protective pathways are not fully understood. Here, we present studies on antioxidant properties of two mono-hydroxyflavone isomers, 3-hydroxyflanove (3HF)- and 7-hydroxyflavone (7HF), against nicotine-associated oxidative stress and injury in cultured renal proximal tubule cells and correlate their antioxidant properties with their chemical structure. Our data clearly demonstrates, for the first time, that while both 3HF and 7HF protect renal cells from NIC-associated cytotoxicity, the mechanism of their action is different: 3HF elicits protective activity via the PKA/CREB/MnSOD pathway while 7HF does so via the ERK/Nrf2/HO-1 pathway. Molecular docking and dynamics simulations with two major signaling pathway proteins showed significant differences in the binding energies of 3HF (-5.67 and -7.39 kcal.mol-1) compared to 7HF (-5.41 and -8.55 kcal.mol-1) in the matrices of CREB and Keap1-Nrf2 proteins respectively, which corroborate with the observed differences in their protective properties in the renal cells. The implications of this novel explorative study is likely to promote the understanding of the mechanisms of the antioxidative functions of different flavones.

Self-recognition of the racemic ligand in the formation of homochiral dinuclear V(V) complex: In vitro anticancer activity, DNA and HSA interaction.

The reaction of a racemic mixture of Schiff base tridentate ligand with vanadium(V) affords homochiral vanadium complex, (VO(R-L))2O and (VO(S-L))2O due to ligand "self-recognition" process. The formation of homochiral vanadium complex was confirmed by 1H NMR, 13C NMR and X-ray diffraction. The HSA- and DNA-binding of the resultant complex is assessed by absorption, fluorescence and circular dichroism (CD) spectroscopy methods. Based on the results, the HSA- and DNA-binding constant, Kb, were found to be 8.0 × 104 and 1.9 × 105 M-1, respectively. Interestingly, in vitro cytotoxicity assay revealed the potent anticancer activity of this complex on two prevalent cancer cell lines of MCF-7 (IC50 value of 14 µM) and HeLa (IC50 value of 36 µM), with considerably low toxicity on normal human fibroblast cells. The maximum cell mortality of 12.3% obtained after 48 h incubation of fibroblast cells with 100 µM of the complex. Additionally, the specific DNA- and HSA-binding was also shown using molecular docking method. The synthesized complex displayed high potential for biomedical applications especially for development of novel and efficient anticancer agents.

Synthesis, characterization and separation of chiral and achiral diastereomers of Schiff base Pd(II) complex: A comparative study of their DNA- and HSA-binding.

A racemic mixture of a new chiral Schiff base ligand (HL: R/S-(1-phenylethylimino)methylnaphtalen-2-ol) has been utilized to prepare Pd(II) complex. Crystallization technique has been employed to separate diastereomeric pairs of Pd(II) complex: (mesoPdL2) and (racPdL2) that in this paper are known as PdL2(1) and PdL2(2), respectively. The synthesized complexes have been characterized by means of elemental analysis (CHN), FT-IR, (1)H and (13)C NMR spectroscopies. Moreover, PdL2(1) has been structurally characterized by single-crystal X-ray diffraction. The geometry around the metal center is square-planar. The interaction of two diastereomers of Pd(II) complex with FS-DNA has been explored, using UV-vis spectroscopy, fluorescence quenching, chemometrics and viscosity measurement methods. The PdL2(1) exhibited higher binding constant, about 10-fold, (1.0×10(6)M(-1)) as compared to PdL2(2) (1.51.5×10(5)M(-1)). Moreover, the human serum albumin (HSA) binding ability has been monitored by absorption, quenching of tryptophan fluorescence emission and circular dichroism (CD) studies. The slight difference is observed between HSA binding affinity with the complexes: PdL2(1) (6.2×10(4)M(-1)) and PdL2(2) (3.3×10(4)M(-1)). Also, the thermodynamic parameters were determined at three different temperatures (298, 308 and 318K). In this study, molecular docking was also carried out to confirm and illustrate the specific DNA- and HSA-binding of the Pd(II) complexes. In the PdL2(1)-HSA system a T-shaped π-π interaction with PHE206 was observed. While in the PdL2(2)-HSA system there are a hydrogen bond, a π-cation and two T-shaped π-π interactions with ASB324, LYS212 and PHE228, respectively. The groove binding mode of DNA interaction has been proposed for both diastereomers.

Synthesis, characterization and biological application of four novel metal-Schiff base complexes derived from allylamine and their interactions with human serum albumin: Experimental, molecular docking and ONIOM computational study.

Novel metal-based drug candidate including VOL2, NiL2, CuL2 and PdL2 have been synthesized from 2-hydroxy-1-allyliminomethyl-naphthalen ligand and have been characterized by means of elemental analysis (CHN), FT-IR and UV-vis spectroscopies. In addition, (1)H and (13)C NMR techniques were employed for characterization of the PdL2 complex. Single-crystal X-ray diffraction technique was utilized to characterise the structure of the complexes. The Cu(II), Ni(II) and Pd(II) complexes show a square planar trans-coordination geometry, while in the VOL2, the vanadium center has a distorted tetragonal pyramidal N2O3 coordination sphere. The HSA-binding was also determined, using fluorescence quenching, UV-vis spectroscopy, and circular dichroism (CD) titration method. The obtained results revealed that the HSA affinity for binding the synthesized compounds follows as PdL2>CuL2>VOL2>NiL2, indicating the effect of metal ion on binding constant. The distance between these compounds and HSA was obtained based on the Förster's theory of non-radiative energy transfer. Furthermore, computational methods including molecular docking and our Own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) were carried out to investigate the HSA-binding of the compounds. Molecular docking calculation indicated the existence of hydrogen bond between amino acid residues of HSA and all synthesized compounds. The formation of the hydrogen bond in the HSA-compound systems leads to their stabilization. The ONIOM method was utilized in order to investigate HSA binding of compounds more precisely in which molecular mechanics method (UFF) and semi empirical method (PM6) were selected for the low layer and the high layer, respectively. The results show that the structural parameters of the compounds changed along with binding to HSA, indicating the strong interaction between the compounds and HSA. The value of binding constant depends on the extent of the resultant changes. This should be mentioned that both theoretical methods calculated the Kb values in the same sequence and are in a good agreement with the experimental data.

Antioxidant activity and ACE-inhibitory of Class II hydrophobin from wild strain Trichoderma reesei.

There are several possible uses of the Class II hydrophobin HFBII in clinical applications. To fully understand and exploit this potential however, the antioxidant activity and ACE-inhibitory potential of this protein need to be better understood and have not been previously reported. In this study, the Class II hydrophobin HFBII was produced by the cultivation of wild type Trichoderma reesei. The crude hydrophobin extract obtained from the fermentation process was purified using reversed-phase liquid chromatography and the identity of the purified HFBII verified by MALDI-TOF (molecular weight: 7.2kDa). Subsequently the antioxidant activities of different concentrations of HFBII (0.01-0.40mg/mL) were determined. The results show that for HFBII concentrations of 0.04mg/mL and upwards the protein significantly reduced the presence of ABTS(+) radicals in the medium, the IC50 value found to be 0.13mg/mL. Computational modeling highlighted the role of the amino acid residues located in the conserved and exposed hydrophobic patch on the surface of the HFBII molecule and the interactions with the aromatic rings of ABTS. The ACE-inhibitory effect of HFBII was found to occur from 0.5mg/mL and upwards, making the combination of HFBII with strong ACE-inhibitors attractive for use in the healthcare industry.