I'm running a simulation of dynamic docking of a set of putative ligands to
a certain receptor.
The receptor's orthosteric site is well-described and quite exposed to the
extracellular solvent.
Every ligand from the set is hydrophobic. Perhaps, due to this, every
simulation ends up with the same result: ligand trying to lose its contact
with solvent, after some random-walking, eventually enters the cavity on
the receptor which leads straight to its orthosteric site and blocks it.
That is ligand blocks the cavity and thus blocks the path to the
orthosteric site for any other compound. Now agonists can't enter the site
and activate the receptor.
Problem is this is not what we see in the experiment. Some compounds from
the set do block the receptor, but others don't - receptor can still be
activated by its agonists.
Even without the experiment, purely on heuristic or logical grounds, the
obtained simulations point to a ridiculous conclusion: that every
hydrophobic compound that sterically matches the cavity will block this
receptor.
I parameterize ligands with gaff2 and set up receptor's amino acids'
protonation states according to the published information.
Any tips on how to make these simulations reflect the reality? Thanks.
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Received on Thu Apr 08 2021 - 01:00:02 PDT
