From: Homeo Morphism (homeo.morphizm_at_gmail.com)
Date: Wed Mar 20 2019 - 13:20:17 CDT
Is there any sense in putting receptor and putative ligand close to each
other and run MD simulation to let ligand explore the receptor's accessible
surface area to possibly find the docking site (or several)?
I've looked through the mailing list and the overall mood is that of
skepticism. But many messages date back to more than 5 years ago, that is
before the super-fast GPUs that we have now. Was this skepticism due to
computational constraints that people were under at the time or are there
more substantial reasons why this shouldn't be attempted, with or without
new-generation hardware?
Here's the particular simulation I would like to try. We have a ligand. We
know experimentally that it activates certain receptor. We have even
narrowed down the area where it docks. And it's in a good agreement with
Autodock results. Now the ligand is modified -- it's appended with another
molecule at its one end. Autodock still docks the original part of the
ligand to the receptor letting the modifier part dangle, but there's every
reason to believe that in reality the modifier part will prevent the
docking. If we only had one modifier part, we could check it
experimentally, but we have more than a few.
But what if I put every one of these modified ligands against the receptor
and let them explore the receptor's surface in NAMD, watching for the most
stable co-conformations, particularly in the area of interest, over
hundreds of nanoseconds, possibly microseconds? How plausible is the whole
approach?
Thanks,
Oleg
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