Development of a ReaxFF reactive force field for ternary phosphate-based bioactive glasses.

Phosphate-based glasses (PBGs) in the CaO-Na2O-P2O5 system have diverse applications as biomaterials due to their unique dissolution properties. A reactive force field (ReaxFF) has been developed to simulate these materials at the atomic level. The ReaxFF parameters of PBGs, including the interaction between phosphorus and calcium atoms, have been developed using a published code based on genetic algorithms. The training data, including the atomic charges, atomic forces, bond and angle parameters, and different differential energies, are chosen and measured from static quantum-mechanical calculations and ab initio molecular dynamics of PBGs. We did different short- and medium-range structural analyses on the bulk simulated PBGs with different compositions to validate the developed potential. Radial and angular distribution functions and coordination numbers of network formers and modifiers, as well as the network connectivity of the glass, are in agreement with experimental and previous simulations using both shell-model classical force fields and ab initio simulated data; for example, the coordination number of phosphorus is 4.0. This successful development of ReaxFF parameters being able to describe the bulk PBGs enables us to work on the dissolution behavior of the glasses, including the interaction of water molecules with PBGs, in future works.

Combined adsorption/regeneration process for the removal of trace emulsified hydrocarbon contaminants.

In this study a process of adsorption and electrochemical regeneration was evaluated for its efficiency in removing low concentrations of emulsified oil from produced water, which is generated as a by-product from the thermal in-situ production of heavy oil. Adsorption behavior was investigated using synthetic model emulsions and samples of produced water; theoretical models were applied to the adsorption equilibrium and kinetics. It was demonstrated that the rate of the adsorption process was controlled by external mass transport, with no contribution from intra-particle diffusion. The non-porous structure of the Graphite Intercalation Compound (GIC) adsorbent led to effective and fast adsorption of oil in less than 30 min. Based on the cryo-SEM imaging and EDX phase mapping, the underlying adsorption mechanism was envisioned in the frame of adhesion and spreading of the emulsified oil droplets on the surface of the predominately hydrophobic GIC surface. The adsorptive capacity of the GIC was 100% recoverable by electrochemical regeneration. Energy consumption for the adsorbent regeneration process was found to be 22 kWh per kg of COD removed for treatment of the synthetic emulsion and 36 kWh per kg of COD for produced water.

Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1.

The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands.

Ligand-selective small molecule modulators of the constitutively active vGPCR US28.

US28 is a broad-spectrum constitutively active G protein-coupled receptor encoded by the human cytomegalovirus (HCMV). It binds and scavenges multiple CC-chemokines as well as CX3CL1 (fractalkine) by constitutive receptor endocytosis to escape immune surveillance. We herein report the design and characterization of a novel library of US28-acting commercially available ligands based on the molecular descriptors of two previously reported US28-acting structures. Among these, we identify compounds capable of selectively recognizing CCL2-and CCL4-, but not CX3CL1-induced receptor conformations. Moreover, we find a direct correlation between the binding properties of small molecule ligands to CCL-induced conformations at the wild-type receptor and functional activity at the C-terminal truncated US28Δ300. As US28Δ300 is devoid of arrestin-recruitment and endocytosis, this highlights the potential usefulness of this construct in future drug discovery efforts aimed at specific US28 conformations. The new scaffolds identified herein represent valuable starting points for the generation of novel anti-HCMV therapies targeting the virus-encoded chemokine receptor US28 in a conformational-selective manner.

Structural and Functional Effect of an Oscillating Electric Field on the Dopamine-D3 Receptor: A Molecular Dynamics Simulation Study.

Dopamine as a neurotransmitter plays a critical role in the functioning of the central nervous system. The structure of D3 receptor as a member of class A G-protein coupled receptors (GPCRs) has been reported. We used MD simulation to investigate the effect of an oscillating electric field, with frequencies in the range 0.6-800 GHz applied along the z-direction, on the dopamine-D3R complex. The simulations showed that at some frequencies, the application of an external oscillating electric field along the z-direction has a considerable effect on the dopamine-D3R. However, there is no enough evidence for prediction of changes in specific frequency, implying that there is no order in changes. Computing the correlation coefficient parameter showed that increasing the field frequency can weaken the interaction between dopamine and D3R and may decrease the Arg128{3.50}-Glu324{6.30} distance. Because of high stability of α helices along the z-direction, applying an oscillating electric field in this direction with an amplitude 10-time higher did not have a considerable effect. However, applying the oscillating field at the frequency of 0.6 GHz along other directions, such as X-Y and Y-Z planes, could change the energy between the dopamine and the D3R, and the number of internal hydrogen bonds of the protein. This can be due to the effect of the direction of the electric field vis-à-vis the ligands orientation and the interaction of the oscillating electric field with the dipole moment of the protein.