AMBER Archive (2006)

Subject: AMBER: Question about interpretation of sander.QMMM results

From: Cenk Andac (
Date: Thu Apr 06 2006 - 14:10:09 CDT

Dear AMBER community,
  I have been trying to develop a derivative of a prescriptional drug using
the sander.QMMM module of AMBER v8. Basically, I don't seem to have
a problem with running sander.QMMM routines.
I have used AM1-BCC charges for my ligands and the Cornell (1995)
charges for the receptor.
I have implemented the sander.QMMM routines both for the ligand-receptor
complexes and the ligands alone in systems solvated by the solvatecap command in leap.
I have extracted the ESCF quantum energy values from my energy outputs and
plotted them out in excel.
I am now at a stage where these ESCF energy values for the complexes
and the respective ligands must be interpreted conscientiously.
  I would like to rank-order binding affinities of the ligand derivatives and
compare these affinities to that of the prescriptional drug in complex with the
receptor, for which an X-Ray structure is available.
  The approach that I am using is as follows
  G(binding)=ESCF(com) - [E(rec)-ESCF(lig)]
  I do not know what E(rec) would be since the recepter is handled by MM.
Therefore, I have been thinking that perhaps it may be possible to compute
relative binding affinities by looking at ESCF(com)-ESCF(lig) only.
Please correct me here if my approach above is wrong!
  In general ESCF values for both the complexes and the ligands gain negative
energy values which I think seem to be OK.
  However there is this particular case where

  ESCF(comp) = ~ -500 kcal and
ESCF(lig) = ~ +100 kcal/mol.
  I guess ESCF(comp) in this case seems to be OK, but why ESCF(lig) would
have a positive energy value? Does this mean the ligand has a solubility problem
or there is something else going on here?
  ESCF(comp) - ESCF(lig) is ~ - 600 kcal/mol which is much greater
than the other ligands complexed to the same binding site.
Could it be possible to conclude that this particular ligand has a higher
affinity to the binding site?
  I would be pleased if you would take some of your time to address the issues
I have outlined above.
  best regards,

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