Tusar Bandyopadhyay

Can Functionalized Cucurbituril Bind Actinyl Cations Efficiently? A Density Functional Theory Based Investigation

The feasibility of using cucurbituril host molecule as a probable actinyl cation binders candidate is investigated through density functional theory based calculations. Various possible binding sites of the cucurbit[5]uril host molecule to uranyl are analyzed and based on the binding energy evaluations, μ(5)-binding is predicted to be favored. For this coordination, the structure, vibrational spectra, and binding energies are evaluated for the binding of three actinyls in hexa-valent and penta-valent oxidation states with functionalized cucurbiturils. Functionalizing cucurbituril with methyl and cyclohexyl groups increases the binding affinities of actinyls, whereas fluorination decreases the binding affinities as compared to the native host molecule. Surprisingly hydroxylation of the host molecule does not distinguish the oxidation state of the three actinyls.

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

AbstractAim:To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE).Methods:We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzymes response during the release of the drugs from its active-site.Results:The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation.Conclusion:Due to excellent cooperative binding of Ortho-7, as rendered by several cation-π interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.

Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: Hydroxylamine anion is predicted to be a better antidote with DFT calculations

Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP-inhibited AChE due to their α-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that α-effect is not so important for dephosphylation reactions. We report the importance of α-effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin-serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin-serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin-serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin-serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this α-nucleophile can be a good antidote agent for the reactivation process.

Solvolysis of chemical warfare agent VX is more efficient with hydroxylamine anion: A computational study

The reaction of the chemical warfare agent VX with hydroxylamine anion (NH(2)O(-)) has been studied using a combination of correlated molecular orbital and density functional theory. It has been found that the hydroxylamine anion leads to predominant formation of non-toxic products for solvolysis of VX. The calculated activation barrier for the rate determining step of hydroxylamine anion with VX was found to be lower than that of hydroperoxidolysis and suggesting a more facile solvolysis with the former alpha-nucleophile. The conformational search was performed for VX using Monte Carlo search method with Merck Molecular force fields (MMFFs), which lead to a more stable conformation than reported. The anomeric effect operates in the lowest energy conformation of VX and contributes towards its stabilization. The reactivity of the alpha-nucleophiles towards VX was correlated well with the corresponding charges on nucleophilic oxygen atoms.

Efficient Separation of Europium Over Americium Using Cucurbit-[5]-uril Supramolecule: A Relativistic DFT Based Investigation.

Achieving an efficient separation of chemically similar Am(3+)/Eu(3+) pair in high level liquid waste treatment is crucial for managing the long-term nuclear waste disposal issues. The use of sophisticated supramolecules in a rigid framework could be the next step toward solving the long-standing problem. Here, we have investigated the possibility of separating Am(3+)/Eu(3+) pair with cucurbit-[5]-uril (CB[5]), a macrocycle from the cucurbit-[n]-uril family, using relativistic density functional theory (DFT) based calculations. We have explored the structures, binding, and energetics of metal-CB[5] complexation processes with and without the presence of counterions. Our study reveals an excellent selectivity of Eu(3+) over Am(3+) with CB[5] (ion exchange free energy, ΔΔGAm/Eu > 10 kcal mol(-1)). Both metals bind with the carbonyl portals via μ(5) coordination arrangement with the further involvement of three external water molecules. The presence of counterions, particularly nitrate, inside the hydrophobic cavity of CB[5], induces a cooperative cation-anion binding, resulting in enhancement of metal binding at the host. The overall binding process is found to be entropy driven resembling the recent experimental observations (Rawat et al. Dalton Trans. 2015, 44, 4246-4258). The optimized structural parameters for Eu(3+)-CB[5] complexes are found to be in excellent agreement with the available experimental information. To rationalize the computed selectivity trend, electronic structures are further scrutinized using energy decomposition analysis (EDA), quantum theory of atom in molecules (QTAIM), Mülliken population analysis (MPA), Nalewajski-Mrojek (NM) bond order, and molecular orbital analyses. Strong electrostatic ion-dipole interaction along with efficient charge transfer between CB[5] and Eu(3+) outweighs the better degree of covalency between CB[5] and Am(3+) leading to superior selectivity of Eu(3+) over Am(3+).

Diffusion influenced end-to-end reaction of a flexible polymer chain: The memory effect

The end-to-end diffusion dynamics of an ideal Rouse chain in solution, as estimated by fluorescence resonance energy transfer between the chain ends via Forster mechanism, is investigated theoretically through a non-Markovian reaction-diffusion equation. The resulting equation, with as well as without the memory term included, is solved numerically and the calculated survival probability, especially in the presence of memory term, compares extremely well with the recently reported Brownian dynamics simulation data for a variety of choice of Forster transfer parameters.

Diffusion influenced reversible transfer of electronic excitation energy in liquid solution by long-range interaction

An approach to donor–acceptor kinetics in the presence of diffusion and reversible energy transfer due to microscopic interaction is described. A set of coupled dynamic equations for the reduced distribution functions of reactant molecules in forward and reverse steps is presented on the basis of a hierarchical system of many-body Smoluchowski equations. With a view toward treating long-range dipolar interaction mediated energy transfer kinetics, this formalism is generalized to incorporate unimolecular decay pathways. Numerical calculations of this set of equations for the excited donor decay after a delta pulse show the dependence of the result on acceptor concentration, forward and back transfer distance-dependent rates, donor and acceptor lifetime, and on their diffusive motion. Comparison with the corresponding forward and irreversible reactive dynamics provides detailed insights into the time dependence of flow of electronic excitation in donors and acceptors. The irreversible Smoluchowski limit is ...

Unbinding free energy of acetylcholinesterase bound oxime drugs along the gorge pathway from metadynamics-umbrella sampling investigation.

Because of the pivotal role that the nerve enzyme, acetylcholinesterase plays in terminating nerve impulses at cholinergic synapses. Its active site, located deep inside a 20 Å gorge, is a vulnerable target of the lethal organophosphorus compounds. Potent reactivators of the intoxicated enzyme are nucleophiles, such as bispyridinium oxime that binds to the peripheral anionic site and the active site of the enzyme through suitable cation–π interactions. Atomic scale molecular dynamics and free energy calculations in explicit water are used to study unbinding pathways of two oxime drugs (Ortho‐7 and Obidoxime) from the gorge of the enzyme. The role of enzyme‐drug cation–π interactions are explored with the metadynamics simulation. The metadynamics discovered potential of mean force (PMF) of the unbinding events is refined by the umbrella sampling (US) corrections. The bidimensional free energy landscape of the metadynamics runs are further subjected to finite temperature string analysis to obtain the transition tube connecting the minima and bottlenecks of the unbinding pathway. The PMF is also obtained from US simulations using the biasing potential constructed from the transition tube and are found to be consistent with the metadynamics‐US corrected results. Although experimental structural data clearly shows analogous coordination of the two drugs inside the gorge in the bound state, the PMF of the drug trafficking along the gorge pathway point, within an equilibrium free energy context, to a multistep process that differs from one another. Routes, milestones and subtlety toward the unbinding pathway of the two oximes at finite temperature are identified. Proteins 2014; 82:1799–1818.

Water-Mediated Differential Binding of Strontium and Cesium Cations in Fulvic Acid

The migration of potentially harmful radionuclides, such as cesium ((137)Cs) and strontium ((90)Sr), in soil is governed by the chemical and biological reactivity of soil components. Soil organic matter (SOM) that can be modeled through fulvic acid (FA) is known to alter the mobility of radionuclide cations, Cs(+) and Sr(2+). Shedding light on the possible interaction mechanisms at the atomic level of these two ions with FA is thus vital to explain their transport behavior and for the design of new ligands for the efficient extraction of radionuclides. Here we have performed molecular dynamics, metadynamics simulations, and density-functional-theory-based calculations to understand the binding mechanism of Sr(2+) and Cs(+) cations with FA. Our studies predict that interaction of Cs(+) to FA is very weak as compared with Sr(2+). While the water-FA interaction is largely responsible for the weak binding of Cs(+) to FA, leading to the outer sphere complexation of the ion with FA, the interaction between Sr(2+) and FA is stronger and thus can surpass the existing secondary nonbonding interaction between coordinated waters and FA, leading to inner sphere complexation of the ion with FA. We also find that entropy plays a dominant role for Cs(+) binding to FA, whereas Sr(2+) binding is an enthalpy-driven process. Our predicted results are found to be in excellent agreement with the available experimental data on complexation of Cs(+) and Sr(2+) with SOM.

Energetics of Ortho-7 (Oxime Drug) Translocation through the Active-Site Gorge of Tabun Conjugated Acetylcholinesterase

Oxime drugs translocate through the 20 Å active-site gorge of acetylcholinesterase in order to liberate the enzyme from organophosphorus compounds’ (such as tabun) conjugation. Here we report bidirectional steered molecular dynamics simulations of oxime drug (Ortho-7) translocation through the gorge of tabun intoxicated enzyme, in which time dependent external forces accelerate the translocation event. The simulations reveal the participation of drug-enzyme hydrogen bonding, hydrophobic interactions and water bridges between them. Employing nonequilibrium theorems that recovers the free energy from irreversible work done, we reconstruct potential of mean force along the translocation pathway such that the desired quantity represents an unperturbed system. The potential locates the binding sites and barriers for the drug to translocate inside the gorge. Configurational entropic contribution of the protein-drug binding entity and the role of solvent translational mobility in the binding energetics is further assessed.