How to Handle Nitrogen Inversion and Membrane-Exposed Binding Sites in Docking
Andrew Orry
Q: I’m working with ligands containing flexible amines. How can I ensure MolSoft explores nitrogen inversions during docking?
A: You can enable this by using the l_samplePyramid flag. In your .dtb configuration file, set: l_samplePyramid = yes
When this is active, the Monte Carlo sampling engine will explicitly include steps to invert the pyramid geometry at nitrogen atoms. This is particularly useful for achieving accurate conformational sampling of uncharged aliphatic amines and sulfonamides.
Q: What is the best way to handle docking when the binding site is located within a lipid bilayer?
A: For sites exposed to a membrane, you should use the l_membraneScore flag. Add the following to your .dtb file: l_membraneScore = yes
Standard VLS scoring assumes an aqueous environment. This flag recalibrates the scoring terms to reflect the low-dielectric nature of a membrane and the fact that the receptor is already "desolvated" by lipids.
Q: How exactly does l_membraneScore change the VLS scoring calculation?
A: It modifies three core components of the scoring function to better simulate a non-aqueous environment:
Solvation Electrostatics (SolEl): It sets all Born radii to a fixed high value. This effectively treats the system as if the high-dielectric medium (water) is too far away to influence the interaction.
H-Bond Desolvation: The donor/acceptor desolvation term (based on accessible surface area) is calculated while excluding receptor desolvation. The logic here is that the receptor atoms are already buried in the membrane and don't need to "shed" water to bind the ligand.
Hydrophobic Term: Similarly, the hydrophobic term excludes the buried receptor surface from the calculation.