[AMBER] TI in Amber and the TUTORIAL A9

From: Marek Maly <marek.maly.ujep.cz>
Date: Mon, 05 Dec 2011 00:42:49 +0100

Hello Thomas,

I have also few questions relating to the tut. A9 and the TI in Amber in

I would like to know how from the MD run in some fixed value of lambda (L)
is possible
to get <dV/dL>. I would naturally assume that two MD runs (first with L
and the second with L + dL) has to
be done from which <V(L)> and <V(L+dL)> are obtained and then <dV/dL>
might be estimated as
( <V(L+dL)> - <V(L)> )/dL or as the ( <V(L+dL,t) - V(L,t)> )/dL where t
is the simulation time.

I also did not understand fully (as it is not explained anywhere) why for
the MD run with the given fixed L value the two simultaneous
sander simulations has to be done for any TI calculation or it.s stage
(one with the prmtop_V0 file and the second with prmtop_V1 file)
and how the data obtained from these two simultaneous simulations are
combined at the end.
Could you please put some light on this ? (e.g. using as the example the
study from your tutorial A9 for
the explanation what is going on in each of that two MD simultaneous
threads during the all three stages)

I can only guess that this approach allow for simultaneous vdw
coupling/decoupling of the different atoms
like in our case in second stage when benzene H6 is decoupled and phenol
O1,H6 atoms are coupled.

So here the first sander thread with prmtop_V0 (with benzene) simulates
probably the system with
benzene using vdw DE-COUPLING formula for all H6-X (H6 from benzene) atom
pairs within the vdw cutoff (except X from the benzene molecule) and
the second sander thread with prmtop_V1 simulates system with phenol using
vdw COUPLING formula with the same lambda
for all O1-X, H6-X (O1, H6 fromphenol) atom pairs within the vdw cutoff
(except X from the phenol molecule).
  Then the energetic data from both threads are combined somehow to mimic
situation when on the one benzene ring simultaneously benzene H6 disappear
and phenol O1,H6 appear. Am I right ?

However this should be also eventually possible to divide into 2 separate
stages ((i)only H6 disappearing and then (ii) only O1,H6 appearing)
with separate dG contributions which together should get the dG of the
simultaneous H6 disappearing and O1,H6 appearing or not ?

Regarding to uncharging of benzene H6 atom stage or the last stage where
O1,H6 phenol atoms are charged I really have no
explanation for two simultaneous sander simulations during the given
lambda run.

I also do not understand why do you have three columns of the graphs here
( http://ambermd.org/tutorials/advanced/tutorial9/analysis.html )
labeled as Step X - Complex, Step X - Water, Step X - Complex-Water where
X is going from 1 to 3.

The number of rows (3) is clear as we have 3 steps ( I) uncharging benzene
H6 II) simultaneous change of benzene H6 to phenol O1,H6 and III) charging
of phenol O1,H6 ) but these three steps are done just in two situations A)
transformed ligands are alone in water B) transformed ligands are
bound to receptor again in water. So I would asume 3 x 2 graphs not 3 x 3
graphs. So could you please explain for me the meaning
of each column ?

Do you think that TI might be possible to use also for the calculation of
the absolute free energy of binding
of the small lignad (L) to the surface of bigger receptor (R) for example
using this scenario.


L bound to R in given water-box.


L and the R separated in the same water-box sufficiently.

(Of course assuming the identical positions of all atoms except L in the
initial files for STARTING and FINAL system)

So I assume that during the whole TI procedure divided into relevant
decoupling/coupling (El.,vdw.) stages
  L continuously "disappear" from it's original position and "appear" on
it's final position
  sufficiently far from the R in the same water box.

Might be this approach OK in your opinion ? If not what is wrong ? How to
improve it if TI could be really useful here ?

BTW do you recommend in such case which I described above to use TI
(however maybe with much more complicated protocol than I suggested)
or is better and also more common to use here Umbrella sampling ?

Thank you very much for your answers in advance !

     Best wishes,



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Received on Sun Dec 04 2011 - 16:00:02 PST
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