[gmx-users] Gromacs Relative Free Energy Calculation Issue

Guanglin Kuang guanglin at kth.se
Mon Oct 3 21:57:14 CEST 2016


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!

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Best Regards!
Guanglin Kuang
KTH-Royal Institute of Technology
School of Biotechnology
Division of Theoretical Chemistry & Biology



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