Atomistic Models of General Anesthetics for Use in in Silico Biological Studies

While small molecules have been used
to induce anesthesia in a
clinical setting for well over a century, a detailed understanding
of the molecular mechanism remains elusive. In this study, we utilize
ab initio calculations to develop a novel set of CHARMM-compatible
parameters for the ubiquitous modern anesthetics desflurane, isoflurane,
sevoflurane, and propofol for use in molecular dynamics (MD) simulations.
The parameters generated were rigorously tested against known experimental
physicochemical properties including dipole moment, density, enthalpy
of vaporization, and free energy of solvation. In all cases, the anesthetic
parameters were able to reproduce experimental measurements, signifying
the robustness and accuracy of the atomistic models developed. The
models were then used to study the interaction of anesthetics with
the membrane. Calculation of the potential of mean force for inserting
the molecules into a POPC bilayer revealed a distinct energetic minimum
of 4–5 kcal/mol relative to aqueous solution at the level of
the glycerol backbone in the membrane. The location of this minimum
within the membrane suggests that anesthetics partition to the membrane
prior to binding their ion channel targets, giving context to the
Meyer–Overton correlation. Moreover, MD simulations of these
drugs in the membrane give rise to computed membrane structural parameters,
including atomic distribution, deuterium order parameters, dipole
potential, and lateral stress profile, that indicate partitioning
of anesthetics into the membrane at the concentration range studied
here, which does not appear to perturb the structural integrity of
the lipid bilayer. These results signify that an indirect, membrane-mediated
mechanism of channel modulation is unlikely.