[gmx-users] Gromacs Relative Free Energy Calculation Issue

[Mark Abraham]

Hi,

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Mark

On Mon, Oct 3, 2016 at 9:57 PM Guanglin Kuang <guanglin at kth.se> wrote:

> Dear Gromacs users,
>
> Has any of you managed to use Gromacs to do relative free energy
> calculations?  I have some technical questions that would need your
> suggestions.
>
> I am trying to reproduce the Amber free energy calculation using PMEMD (
> http://ambermd.org/tutorials/advanced/tutorial9/#overview).
>
> First, I generated the topology and coordinate files of the ligands
> (benzene and phenol) using alchemistry_setup.py, developed by Dr. David
> Mobley (https://github.com/MobleyLab/alchemical-setup), as well as
> antechamber with AM1/BCC charge.
>
> Then I set up the mdp file and topology file for relative free energy
> calculations. I used the single topology together with the one-step and
> three-step transformations, respectively. Please have a look at the
> relevant files  attached for the details.
>
> Finally, I used g_bar to calculate the free energy
> (alchemistry_analysis.py can give similar results). From the results I
> found that one-step transformation can give good results, only if some
> restraints are applied to the protein-ligand complex, because I found that
> benzene/phenol are not strong binders to lyszome, and would drift around in
> the binding pocket, thus give poor results deviating from experimental
> data. However, in the three-step strategy, the results are much worse, this
> is probably due to the fact that a dual topology is used in Amber but a
> single topology is used in Gromacs (my case), we may not be able to do the
> changes directly (as shown in the attached topology files).
>
> Even though one-step transformation seems to give a better result in this
> case, it may be due to luck, because it is suggested that one-step
> transformation is usually not as good as three-step transformation, and can
> even give misleading results in some occasions (what occasions?).
>
> Therefore, could any experienced users of relative free energy calculation
> have a look at my set-up and point out the problems? I would appreciate any
> improvement to the set-up!
>
> Thank you!
>
>
> -----------------------------------------------------------------------------------------------------------------------------------------------------------
> Best Regards!
> Guanglin Kuang
> KTH-Royal Institute of Technology
> School of Biotechnology
> Division of Theoretical Chemistry & Biology
>
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