Dear prof. Case, Thomas, Adrian and all,
first of all thanks a lot for your prompt comments !
It seems that there is no chance to escape from "restraint usage" if one
would like to use
TI for estimation of the absolute free binding energies.
If I understood well the problem of my suggested approach is that from the
individual processes "i" is
not possible to construct pathway with fully decoupled ligand on one end
and the fully
interacting ligand on the other end and my "simplification" of decoupling
dG
(without any additional corrections) might be probably comparable with
it's reduction just on it's enthalpic part.
It's clear that I wanted (as the TI beginner) to prevent me form restraint
use as of course their careful
choice/application and final removal of their contribution from the
calculated dG is probably another
potential source of wrong results (especially for beginners) also
considering here the fact that the relevant Amber tutorial
is not available (if I am not wrong) at the moment.
Meanwhile I checked article (mentioned several times in Amber forum):
------------------------------------------------------------------------------------
Yuqing Deng and Benoit Roux, Calculation of Standard Binding Free
Energies: Aromatic
Molecules in the T4 Lysozyme L99A Mutant,J. Chem. Theory Comput. 2006, 2,
1255-1273
------------------------------------------------------------------------------------
Here translantional Ut (between centers of masses of L and R) and
rotational Ur restraining
potentials were used during the decoupling of L from R. The effect of
these both restraints
was consequently substracted using among others dGs of elimination of
these restraints in situation when ligand fully
interact with receptor.
The full correction component for the final absolute binding energy which
arises from the restraints use
is formulated here as follows:
dGrestr_corr = ddGt + ddGr
where:
ddGt = -dGt_site - kB*T*ln(Ft*C0)
ddGr = -dGr_site - kB*T*ln(Fr*C0)
where (dGt_site, dGr_site) are above mentioned dGs of elimination of the
translational, rotational restrains using
appropriate lambda-anihilation processes, C0 is standard concentration 1
mol/L and Ft and Fr are translational and rotational factors expressed
in this article just in analytical/integral form.
So let say that I got some overal idea but for successful application of
this strategy for my problem using TI as implemented in Amber11
I would for sure appreciated some more information related mainly to the
process of slow restraints "anihilation" -
calculation of ddGt and ddGr in practice.
Thanks in advance for any relevant comments !
Best wishes,
Marek
Dne Tue, 03 Jan 2012 10:26:37 +0100 <steinbrt.rci.rutgers.edu> napsal/-a:
> Hi,
>
>> If the ligand L is not too small and several it's atoms are reasonably
>> involved into binding interaction with receptor (so it is not the case
>> of
>> just
>> one h-bond etc.) the ligand migt be reasonably divided into several
>> disjoint atom groups G1,G2 ...Gn and the total decoupling free energy dG
>> might be
>> in my opinion calculated as dG = dG(G1) + dG(G2) + ... +dG(Gn) where
>> dG(Gi) is the free energy contribution corresponding with decoupling of
>> the
>> atom group Gi while the rest of the ligand (L-Gi) remains fully
>> interacting (and for each "i" plays the role of "natural" restraint).
>
> What you would need to do is decouple each individual part i of the
> ligand
> after the other, without switching on parts 1 to i-1 again, then the sum
> of your transformations would be equal to the total dG(Bind). The last
> bit
> would again need restraints though. The ligand gaining/losing
> translational and rotational degrees of freedom is actually an important
> part of the binding process that should be accounted for. Restraints are
> a
> way to do this but your approach wouldn't do the same I believe.
>
> Summarily, a ligand is more than the sum of its parts ;-)
>
> Kind Regards,
>
> Thomas
>
> Dr. Thomas Steinbrecher
> formerly at the
> BioMaps Institute
> Rutgers University
> 610 Taylor Rd.
> Piscataway, NJ 08854
>
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Received on Tue Jan 03 2012 - 11:00:02 PST
