AMBER Archive (2006)


From: Thomas Cheatham (
Date: Thu Aug 10 2006 - 18:57:34 CDT

> I have carried out hbond analysis on an androgen receptor (pdb 1e3g) bound to
> 4 different ligands (2 steroidal and 2 non-steroidal). I get results that are
> consistent with those quoted in literature, for all of my complexes, except
> for the case in which the receptor is bound to the non steroid vinclozolin.
> Here, no hbonds are found over a 4820 ps trajectory between the ligand and
> the active site amino acids. I want to verify that this is indeed the case- ie
> that the fact that no hbonds are being observed is not due to default cutoffs.
> It has been suggested to me that I could constrain hbonds, re-run some
> dynamics and repeat the hbond analysis. I am not quite sure how to go about
> this, and would appreciate some help.

First of all, there are many reasons beyond possible cutoff artifacts
(either in terms of cutoff of the electrostatics or default hbond distance
cutoff) why the ligand may not show what you expect to see. Random
fluctuations could lead to unbinding, the drug may not be initially bound
where you think it is, it may shift binding modes during the
simulation, etc. You will have to "look" at the results, i.e. visualize
the trajectory and carefully monitor whatever you can to provide more

In your case, I would not rely solely on the hbond analysis (which is
really meant for providing an aggregate picture about potential
interactions beyond which one would want to monitor individually), but
actually measure the distance between the groups of interest.

  distance d1 out d1.dat mask1 mask2

will measure the distance between the centers of mass of the atoms in each
mask/atom specification (w/ ptraj).

If you indeed see that it is not bound as expected, it could be due to any
number of artifactual or real phenomena. If it was initially bound in a
known (i.e. experimental) geometry, then I would pursue the tact of trying
to restrain it during equilibration. [Note this is a "restraint" as
opposed to a fixed constraint which would require some sort of SHAKE
constraint and is not necessary]. You can restrain specific distances
with with NMR facility, nmropt=1, and specification of additional input
that describes the bond lengths between arbitrary (groups of) atoms you
wish to restrain. The manual has examples, as does the DNA NMR refinement
tutorial (but this is probably overkill). If the system is reasonably
well-equilibrated with restraints and then the drug consistently moves
away (observed more than once!) this may be suggestive. Also, one could
try MM-PBSA analysis to see if the binding affinity is decreased with this
particular drug.


\-/ Thomas E. Cheatham, III (Assistant Professor) College of Pharmacy
-/- Departments of Med. Chem. and of Pharmaceutics and Pharm. Chem.
/-\ Adjunct Asst Prof of Bioeng.; Center for High Performance Computing
\-/ University of Utah, 30 S 2000 E, SH 201, Salt Lake City, UT 84112
/-\ (801) 587-9652; FAX: (801) 585-9119
\-/ BPRP295A

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