Effect of the interfacial tension and ionic strength on the thermodynamic barrier associated to the benzocaine insertion into a cell membrane.

The insertion of local anaesthetics into a cell membrane is a key aspect for explaining their activity at a molecular level. It has been described how the potency and response time of local anaesthetics is improved (for clinical applications) when they are dissolved in a solution of sodium bicarbonate. With the aim of gaining insight into the physico-chemical principles that govern the action mechanism of these drugs at a molecular level, simulations of benzocaine in binary lipid bilayers formed by DPPC/DPPS were carried out for different ionic strengths of the aqueous solution. From these molecular dynamic simulations, we observed how the thermodynamic barrier associated with benzocaine insertion into the lipid bilayers diminished exponentially as the fraction of DPPS in the bilayer increased, especially when the ionic strength of the aqueous solution increased. In line with these results, we also observed how this thermodynamic barrier diminished exponentially with the phospholipid/water interfacial tension.

Binding of glutamate to the umami receptor.

The umami taste receptor is a heterodimer composed of two members of the T1R taste receptor family: T1R1 and T1R3. It detects glutamate in humans, and is a more general amino acid detector in other species. We have constructed homology models of the ligand binding domains of the human umami receptor (based on crystallographic structures of the metabotropic glutamate receptor of the central nervous system). We have carried out molecular dynamics simulations of the ligand binding domains, and we find that the likely conformation is that T1R1 receptor protein exists in the closed conformation, and T1R3 receptor in the open conformation in the heterodimer. Further, we have identified the important binding interactions and have made an estimate of the relative free energies associated with the two glutamate binding sites.

Physicochemical study of the acetonitrile insertion into polypyrrole films.

A study by molecular dynamics (MD) simulation of the acetonitrile diffusion into a polypyrrole film was carried out with atomic detail in a 0.1N lithium perchlorate solution. From the simulated trajectories, the acetonitrile behavior was estimated from bulk solution to the interior of the polypyrrole film, across the polypyrrole/solution interface, for a neutral (reduced) and charged (oxidized) state of the polymer. Among other properties, the translational diffusion coefficient and rotational relaxation time of the acetonitrile were calculated, where a diminution in the translational diffusion coefficient was measured in the interior of the polypyrrole matrix compared to bulk, independently of the oxidation state of the polymer, in contrast with the behavior of the rotational relaxation time that increases from bulk to the interior of the polymer for both oxidation states. In addition, the difference of free energy DeltaG associated to the acetonitrile penetration into the polymer was calculated. From the results, it was evidenced that the scarce affinity of acetonitrile to diffuse into the polymer in its reduced state is related with the positive uniform difference of free energy DeltaG approximately 20 kJ/mol, while in the oxidized state, an important free energy barrier of DeltaG approximately 10 kJ/mol has to pass trough for reaching stable sites inside the polymer with values of DeltaG up to -10 kJ/mol.

Study of the benzocaine transfer from aqueous solution to the interior of a biological membrane.

The precise molecular mechanism of general anesthetics remains unknown. It is therefore important to understand where molecules with anesthetic properties localize within biological membranes. We have determined the free energy profile of a benzocaine molecule (BZC) across a biological membrane using molecular dynamics simulation. We use an asymmetric phospholipid bilayer with DPPS in one leaflet of a DPPC bilayer (Lopez Cascales et al. J. Phys. Chem. B 2006, 110, 2358-2363) to model a biological bilayer. From the free energy profile, we predict the zone of actuation of a benzocaine is located in the hydrocarbon region or at the end of the lipid head, depending of the presence of charged lipids (DPPS) in the leaflet. We observe a moderate increase in the disorder of the membrane and in particular an increase in the disorder of DPPS. Static and dynamic physicochemical properties of the benzocaine, such as its dipole orientation, translational diffusion coefficient, and rotational relaxation time were measured.