Dear all,
I am trying to utilize TI in amber in our medicinal chemistry project. I
successfully did tutorial of transforming benzene to phenol, but I am
struggling for a week with my system.
Problem is that ligands have higher tendency to immediately leave
binding site after releasing restraints at higher lambda values.
My workflow is:
10000 steps of minimization (min.in)
50 ps heating with restrained solute heavy atoms with force constant 100
(heat.in)
50 ps npt with restrained solute heavy atoms with force constant 100
(equil1.in)
100 ps npt with restrained solute heavy atoms with force constant 10
(equil2.in)
100 ps npt with restrained protein backbone and core TI region with
force constant 10 (equil3.in)
100 ps npt with restrained protein backbone and core TI region with
force constant 1 (equil4.in)
100 ps npt without restraints (prod.in)
See attached files.
My plan was to use this small production run with 0.5 lambda to generate
starting structures for other runs and windows, but for most of tried
ligands, I am getting them out of pocket in first few picoseconds even
at lambda 0.5.
I know that both endstates are stable under normal MD for 100 ns without
problem. If I perform whole workflow for lambda 0.1 and 0.9 - the
production with 0.1 is stable. If I switch ligands and repeat procedure
again production with lambda 0.1 is stable, but of course with different
ligand as more dominant. I tried to play with number of steps during
preparation, different SHAKE settings, using CPU or GPU code and more
with no luck.
I think I am missing something important :) Any help would be appreciated.
Juraj Dobias
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Received on Wed Apr 08 2020 - 14:00:02 PDT
