Hi Hannes,
Thanks for the suggestion.
I scratched out 3 possible cycles can be considered.
For the dGcomplex term,
Cycle 1 has a twice large perturbation in one calculation as in cycle 2. The error might be smaller in the multiple-step transformation.
For the dGligand term,
in cycle 1 and 2, two ligands are put into solution, and there is a concern about the dimerization.
However, in cycle 3, one ligand is in solution, there is a difference in entropy.
I'm thinking how to run the ligand transformation in solution, using AA/AB/BB or (A+A)/(A+B)/(B+B)? The parameterization steps will be different to keep the dimer state.
The dimerization is related to binding mechanism. If the ligand itself doesn't dimerize in experiment, does that mean we don't need to consider the A+A->AA transformation? and simply using (A+A) will do the work?
Cycle 1:
P+AA->P-AA
| | |
P+BB->P-BB
Cycle 2:
P+AA->P-AA
| | |
P+AB->P-AB
| | |
P+BB->P-BB
Cycle 3:
P+A->PA
| | |
P+B->PB
PA+A->PA-A
| | |
PA+B->PA-B
(transform to)
PB+A->PB-A
| | |
PB+B->PB-B
Yuan
-----Original Message-----
From: Hannes Loeffler [mailto:Hannes.Loeffler.stfc.ac.uk]
Sent: Saturday, June 04, 2016 6:01 AM
To: amber.ambermd.org
Subject: Re: [AMBER] TI calculation with ligand dimer
On Fri, 3 Jun 2016 18:39:31 -0400
"Hu, Yuan" <yuan.hu.merck.com> wrote:
> I'm interested in calculation the relative binding free energy of
> mutating a ligand dimer AA into dimer BB, where the ligand in the
> dimer has non-covalent interaction with each other, and both fit into
> the same protein pocket. Considering a single atom mutation from
> A->B, is it possible to use TI to calculate the relative binding free
> energy of AA-->BB transformation? What will be the right way to do
> it? Any thoughts or literature references will be appreciated. Thanks.
I don't think there is a "right" way. Technically, you can go
straight from AA to BB in one "step". One question though is how
disruptive this double mutation would be and whether it wouldn't be
better to do AA->AB (or AA->BA).
I would probably look into several variants to see if the overall
thermodynamic cycle is in agreement with the sum of a smaller subset of
cycles. E.g. will AA->AB->BB and AA->BA->BB give the same result as
AA->BB. The subset steps may also give additional insight.
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Received on Mon Jun 06 2016 - 08:00:03 PDT
