Syed Tarique Moin

A Quantum Mechanical Charge Field Molecular Dynamics Study of Fe2+ and Fe3+ Ions in Aqueous Solutions

Ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) simulations have been performed for aqueous solutions of Fe(2+) and Fe(3+) ions at the Hartree-Fock level of theory to describe and compare their structural and dynamical behavior. The structural features of both hydrated ions are characterized by radial distribution functions that give the maximum probability of the ion-O distance for Fe(2+) and Fe(3+) ions at 2.15 and 2.03 A, respectively. The angular distribution functions of both ions prove the octahedral arrangement of six water ligands, whereas the second shells of these ions differ. Both ions show influence on the water molecules beyond the second shells. The structure-forming abilities of both ions are visible from the ligand mean residence times and ion-O stretching frequencies evaluated for both ions. The substantially improved data obtained from these QMCF-MD simulations show better correlation with available experimental results than the conventional quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) approaches with one hydration shell treated by quantum mechanics.

Activation of TrkB receptors by NGFβ mimetic peptide conjugated polymersome nanoparticles

Activation of tyrosine kinase receptor B (TrkB), a neurotrophin receptor, has been shown to increase neuronal cell survival and promote regeneration. Stimulation of the TrkB receptor by neurotrophic growth factors has been identified as a possible therapeutic target for the treatment of neurodegenerative disorders. However, growth factor delivery is problematic because of a short half-life in vivo. We have conjugated hNgf-EE, a short peptide mimetic of NGFβ to the surface of polymersome nanoparticles and shown that they are capable of activating the TrkB receptor in vitro in the SHSY-G7 cell line. We propose that polymersomes could act as a scaffold for the delivery of TrkB activating moieties and that the polymersome size and polyethylene glycol surface have been shown to increase in vivo retention time. These multifunctional nanoparticles have potential for the treatment of neurodegenerative disorders by TrkB activation. From the ClinicaL Editor: Tyrosine kinase receptor B activation has been shown to promote regeneration and survival of neurons. However, growth factor delivery to stimulate these receptors remains problematic. The authors demonstrate that a peptide mimetic of NGFβ conjugated to the surface of polymersome nanoparticles is capable of activating the TrkB receptors. These nanoparticles may offer a novel treatment strategy for a variety of neurodegenerative disorders.

2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors☆

Twenty-five derivatives of 2-arylquinazolin-4(3H)-ones (1-25) were evaluated for their yeast (Saccharomyces cerevisiae) α-glucosidase inhibitory activities. All synthetic compounds, except 1 and 6, were found to be several hundred fold more active (IC50 values in the range of 0.3±0.01-117.9±1.76μM), than the standard drug, acarbose (IC50=840±1.73μM). The enzyme kinetic studies on the most active compounds 12, 4, 19, and 13 were performed for the determination of their modes of inhibition and dissociation constants Ki. Study of the modes of inhibition of compounds 12, and 4 were also performed using molecular modeling techniques. In brief, current study identifies a novel class of α-glucosidase inhibitors which can be further studied for the treatment of hyperglycemia and obesity.

Sulfur dioxide in water: structure and dynamics studied by an ab initio quantum mechanical charge field molecular dynamics simulation.

An ab initio Quantum Mechanical Charge Field Molecular Dynamics Simulation (QMCF MD) was performed to investigate structure and dynamics behavior of hydrated sulfur dioxide (SO(2)) at the Hartree-Fock level of theory employing Dunning DZP basis sets for solute and solvent molecules. The intramolecular structural characteristics of SO(2), such as S═O bond lengths and O═S═O bond angle, are in good agreement with the data available from a number of different experiments. The structural features of the hydrated SO(2) were primarily evaluated in the form of S-O(wat) and O(SO(2))-H(wat) radial distribution functions (RDFs) which gave mean distances of 2.9 and 2.2 Å, respectively. The dynamical behavior characterizes the solute molecule to have structure making properties in aqueous solution or water aerosols, where the hydrated SO(2) can easily get oxidized to form a number of sulfur(VI) species, which are believed to play an important role in the atmospheric processes.

Dynamics of ligand exchange mechanism at Cu(II) in water: An ab initio quantum mechanical charge field molecular dynamics study with extended quantum mechanical region

Ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) were successfully applied to Cu(II) embedded in water to elucidate structure and to understand dynamics of ligand exchange mechanism. From the simulation studies, it was found that using an extended large quantum mechanical region including two shells of hydration is required for a better description of the dynamics of exchanging water molecules. The structural features characterized by radial distribution function, angular distribution function and other analytical parameters were consistent with experimental data. The major outcome of this study was the dynamics of exchange mechanism and reactions in the first hydration shell that could not be studied so far. The dynamical data such as mean residence time of the first shell water molecules and other relevant data from the simulations are close to the results determined experimentally. Another major characteristic of hydrated Cu(II) is the Jahn-Teller distortion which was also successfully reproduced, leading to the final conclusion that the dominating aqua complex is a 6-coordinated species. The ab initio QMCF-MD formalism proved again its capabilities of unraveling even ambiguous properties of hydrated species that are far difficult to explore by any conventional quantum mechanics/molecular mechanics (QM/MM) approach or experiment.

Molecular dynamics simulation of mammalian 15S-lipoxygenase with AMBER force field.

A molecular dynamics simulation study of mononuclear iron 15S-lipoxygenase (15S-LOX) from rabbit reticulocytes was performed to investigate its structure and dynamics; newly developed AMBER force field parameters were employed for the first coordination sphere of the catalytic iron (II). The results obtained from this study demonstrate that the structural features of the catalytic iron coordination site are in good agreement with available data obtained from experiments. The motional flexibility of the N-terminal β-barrel domain is greater than the C-terminal catalytic domain; flexibility was assessed in terms of B-factors and secondary structure calculations. The significant features obtained for the relative motional flexibility of these two domains of 15S-LOX in solution as well as the isolated C-terminal domain were analyzed in terms of radius of gyration and maximum diameter, which correlated well with the structural flexibility of 15-lipoxygenase-1 in solution as probed by small-angle X-ray scattering. The motional flexibility indicates interdomain motion between the N-terminal β-barrel and the C-terminal catalytic domain; this was further verified by the evaluation of central bending in the solvated LOX molecule, which identified an unstructured stretch of amino acids as the interdomain linker. The average bending angle confirmed significant central bending between these two domains, which was linked to the high degree of motional freedom of the N-terminal β-barrel domain in aqueous solutions. This can be considered to have biological relevance for membrane binding as well as for regulating the catalytic domain.

Solvent-free click chemistry for tetrazole synthesis from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-Based fluorinated ionic liquids, their micellization, and density functional theory studies

In the present study, we have synthesized novel 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-based fluorinated ILs (DBUF-ILs) simply by solvent-free quaternization and subsequent anion (F−) exchange reactions. The micellization behavior and density functional theory (DFT) calculations of DBUF-ILs have been conducted. The DFT calculations of some selected DBU derivatives show the N-substitution effect on DBU geometry. In addition to the geometry analysis of these DBU derivatives, HOMO and LUMO energies, and band gaps were also calculated which give insight into different types of transitions and electronic effects. The stability of the DBU derivatives was also investigated via binding energy calculations based on the DFT method. A click chemistry reaction for tetrazole formation is performed under solvent-free thermal and microwave irradiation. The yields obtained were in the range of 70–95%. Complete structural characterization of each product was accomplished by several modern techniques including 1H NMR, 13C NMR, EI+ and/or FAB mass spectrometry, IR and UV spectroscopy.

Structure and dynamics of methanol in water: A quantum mechanical charge field molecular dynamics study

An ab initio quantum mechanical charge field molecular dynamics simulation was carried out for one methanol molecule in water to analyze the structure and dynamics of hydrophobic and hydrophilic groups. It is found that water molecules around the methyl group form a cage‐like structure whereas the hydroxyl group acts as both hydrogen bond donor and acceptor, thus forming several hydrogen bonds with water molecules. The dynamic analyses correlate well with the structural data, evaluated by means of radial distribution functions, angular distribution functions, and coordination number distributions. The overall ligand mean residence time, τ identifies the methanol molecule as structure maker. The relative dynamics data of hydrogen bonds between hydroxyl of methanol and water molecules prove the existence of both strong and weak hydrogen bonds. The results obtained from the simulation are in excellent agreement with the experimental results for dilute solution of CH3OH in water. The overall hydration shell of methanol consists in average of 18 water molecules out of which three are hydrogen bonded.

Solvent-free 1H-tetrazole, 1,2,5,6-tetrahydronicotinonitrile and pyrazole synthesis using quinoline based ionic fluoride salts (QuFs): thermal and theoretical studies

The role of ionic liquids as catalyst and solvent to mediate organic reactions is well documented. While imidazole and pyridine-based ionic liquids have traditionally been the ionic liquids of choice for organic synthesis, imidazoles inert nature and pyridines toxicity are often viewed as impediments. In the present study, we have synthesized ionic liquids (QuFs), employing the non-toxic quinoline ring. The desired QuFs were readily prepared via N-alkylation and corresponding anion exchange with fluoride ions. The structures of the synthesized QuFs were confirmed with advanced spectroscopic techniques such as 1H and 13C NMR, IR and mass spectrometry. The potential of these newly synthesized QuFs as catalyst for click chemistry and other reactions was explored by carrying out synthesis of 5-(p-methylphenyl)-1H-tetrazole (7), 2-dicyanomethylene-6-methyl-4,6-bis(m-methoxyphenyl)-1,2,5,6-tetrahydronicotinonitrile (12), and 3,5-dimethyl-1-(p-methoxy)-1H-pyrazole (15). Detailed thermal analysis (DSC, TGA and DTG) was carried out to study the thermal stability of synthesized QuFs. Density functional theory (DFT) calculations and molecular dynamics simulations were also carried in order to establish a relationship between binding energies, and structural and dynamic characteristics of QuFs.

Dynamic changes in the secondary structure of ECE-1 and XCE account for their different substrate specificities

BackgroundX-converting enzyme (XCE) involved in nervous control of respiration, is a member of the M13 family of zinc peptidases, for which no natural substrate has been identified yet. In contrast, it’s well characterized homologue endothelin-converting enzyme-1 (ECE-1) showed broad substrate specificity and acts as endopeptidase as well as dipeptidase. To explore the structural differences between XCE and ECE-1, homology model of XCE was built using the complex structure of ECE-1 with phosphoramidon (pdb-id: 3DWB) as template. Phosphoramidon was docked into the binding site of XCE whereas phosphate oxygen of the inhibitor was used as water molecule to design the apo forms of both enzymes. Molecular dynamics simulation of both enzymes was performed to analyze the dynamic nature of their active site residues in the absence and presence of the inhibitor.ResultsHomology model of XCE explained the role of non-conserved residues of its S2’ subsite. Molecular dynamics (MD) simulations identified the flexible transitions of F149/I150, N566/N571, W714/W719, and R145/R723 residues of ECE-1/XCE for the strong binding of the inhibitor. Secondary structure calculations using DSSP method reveals the folding of R145/R723 residue of ECE-1/XCE into β-sheet structure while unfolding of the S2’ subsite residues in aECE-1 and sustained compact folding of that of aXCE. The results evaluated are in good agreement with available experimental data, thus providing detailed molecular models which can explain the structural and specificities differences between both zinc peptidases.ConclusionsSecondary structure changes of both enzymes during the simulation time revealed the importance of β-sheet structure of R145/R723 for its binding with the terminal carboxylate group of the inhibitor. Unfolding of the α-helix comprising the S2’ subsite residues in aECE-1 correlate well with its endopeptidase activity while their compact folding in aXCE may account for the inactivity of the enzyme towards large C-terminal containing substrates.