Membrane Permeability

The membrane permeability tool allows you to calculate the passive membrane permeability of a set of molecules. It is primarily intended for use on congeneric series of ligands to evaluate the relative permeability of similar ligands. The membrane permeability facility has a special sampling method for macrocycles, which is used automatically.

The calculations are based on a physical model with the assumptions that the permeability is dominated by the free energy of desolvation and change of state (neutralization and tautomerization) on passing into the membrane. The membrane is modeled as a low-dielectric continuum, and water as a high-dielectric continuum. A conformational search is performed in the low-dielectric continuum and the low-energy conformers are evaluated and scored in the high-dielectric continuum. Macrocycles are handled with a specialized sampling method. The highest value of the permeability found from this ensemble is used as the permeability for that molecule. In addition to this approach, another approach is used in which the model is optimized to reproduce RRCK permeability assay results, with fitted energy and volume terms.

For a fuller description of the background and methodology, see the following references:

Leung, S. S. J.; Mijalkovic, J.; Borrelli, K.; Jacobsen, M. J. Chem. Inf. Model. 2012, 52, 1621. DOI: 10.1021/ci200583t.
Leung, S. S. J.; Sindhikara, D.; Jacobsen, M. J. Chem. Inf. Model.2016, 56, 924. DOI: 10.1021/acs.jcim.6b00005.

The calculations can take several minutes per molecule. The molecules should be all-atom 3D structures in a reasonable geometry. You can use LigPrep to convert 2D structures or SMILES strings to 3D structures—see the LigPrep User Manual — Contents for details.

The calculations can be set up and run from the Membrane Permeability Panel: to open it, click the Tasks button and browse to ADME and Molecular Properties → Physics-Based Membrane Permeability.

The main results of the calculation are the structures of the ligands in the conformation that is predicted to be the most likely conformation inside the membrane, and four Maestro free energy properties, given in kcal/mol. The ligands are scored with a function that is optimized to predict RRCK permeability assay results. This score is also added as a property, which is the logarithm of the permeability in cm/s. The output properties are described in Table 1.

Table 1. Membrane permeability properties.
Property	Description
Log Perm RRCK	Logarithm of the RRCK permeability in cm/s. This property is optimized to reproduce RRCK permeability assay results, with fitted energy and volume terms.
Membrane dG Insert	The total free energy penalty for the ligand to change state and enter the membrane. This is the sum of Membrane HDLD and Membrane StatePenalty, described below.
Membrane Energy	The energy in the membrane environment. Membrane HDLD = Membrane Energy - Solvent Energy.
Membrane GB	An alternative form of calculating Membrane Energy that uses a constant solvent radius for the membrane and water environments. The initial paper used a chloroform and a water model that differed in both their dielectric and their solvent radius, but it was believed that the difference in solvent radius was the only important part so this received the bulk of the explanation in the paper. However when we tried to remove the difference in the solvent radius, the results got subtly worse. Our current hypothesis is that the effective solvent radius in the membrane is actually larger than it would be in water because the lipids cannot work themselves into all of the crevices in a given ligand structure. We include it in the output properties for completeness, but in we have achieved better results with including differences in both solvent radius and dielectric.
Membrane HDLD (high dielectric region to a low dielectric region)	The free energy penalty for the neutral form of the ligand in its conformation inside the membrane to enter the membrane (i.e., move from the high dielectric region to the low dielectric region).
Membrane HDLD GB	An alternative form of calculating Membrane HDLD that uses a constant solvent radius for the membrane and water environments (see Membrane Energy for details). Membrane HDLD GB = Membrane GB - Solvent GB.
Membrane Penalty	Energy penalty for neutralizing and tautomerizing the ligand.
Membrane StatePenalty	The free energy penalty for neutralizing (or tautomerizing) the ligand.
Solvent Energy	The energy in the solvent environment. Membrane HDLD = Membrane Energy - Solvent Energy.
Solvent GB	An alternative form of calculating Solvent Energy that uses a constant solvent radius for the membrane and water environments (see Membrane Energy for details).
Volume	The volume of ligand in its low-dielectric conformation.

You can visualize the contributions to the Membrane HDLD property by atom in the Prime Energy Visualizer Panel: to open it, click the Tasks button and browse to Biologics → Visualize Energy.

In the Visualize section of the panel, choose Membrane Permeability from the Family option menu. Only one property is shown, labeled Total Membrane Permeability.

To visualize this property on a ligand, include the ligand in the Workspace and click Update Workspace. The ligand is colored according to the contribution of each atom to the permeability. If you want to step through the ligands that you calculated the property for to visualize each in turn, select Automatically update Workspace. You can then use the left and right arrow keys to step through the ligands in the Project Table.

The visualization allows you to locate parts of the ligand that are most important for the membrane permeability. It could also help to identify parts of the ligand that you might want to modify to increase or decrease the permeability.

See Visualizing Prime Energy Terms for more information on the Prime Energy Visualizer panel.

If you want to run the calculation from the command line, you can use the following command:

structurebased_adme permeability Command Help structure_file

See Running Schrödinger Applications from the Command Line for information on running jobs from the command line, and structurebased_adme permeability Command Help for command options.