Simulations of gasotransmitter permeation through lipid bilayers

The permeation of gasotransmitter molecules, NO, CO and H₂S, through phospholipid bilayers were studied using molecular dynamics simulations in order to gain insight into the process by which these solutes cross biological membranes. These simulations require accurate representations of both lipids and water components of the simulation. The CHARMM36 lipid model is generally effective at predicting the properties of lipid bilayers, but this model was developed for use with CHARMM TIP3P water model. This water model overestimates the dielectric constant and diffusion coefficient of water, which introduces error into the permeability calculations. The TIP3P-FB and TIP4P-FB water models are more accurate in predicting the dielectric constant and transport properties of water, which could allow for more realistic simulations of membrane permeation. To validate whether these water models are compatible with the CHARMM36 lipid model, the lipid headgroup area, compressibility, order parameters, and scattering form factors were calculated using these models and were generally found to be in good agreement with the experimental values. This indicates that the CHARMM36 model can be used with either of these water models without modification. Using the TIP4P-FB water model and the CHARMM36 lipid force field, the permeation of NO, CO, and H₂S through a POPC lipid bilayer was simulated. These simulations show that the Gibbs energy barriers to permeation are modest for all three gasotransmitters, allowing them to permeate membranes readily. High rates of permeation for NO and H₂S were calculated using the inhomogeneous solubility-diffusion model, in good agreement with experiments. Although no experimental value has been reported, the rate of CO permeation was found to be similar to that of NO. The effect of cholesterol content in the bilayer was also investigated and was found to lower the rates of permeation modestly