# Free energy verification by thermodynamic integration in liquid solutions

**URL:** <https://gromacs.bioexcel.eu/t/free-energy-verification-by-thermodynamic-integration-in-liquid-solutions/13141>\
**Category:** User discussions\
**Tags:** mdp-parameters, analysis-tools, free-energy\
**Created:** [January 22, 2026, 7:46pm UTC](https://gromacs.bioexcel.eu/t/free-energy-verification-by-thermodynamic-integration-in-liquid-solutions/13141 "2026-01-22T19:46:49Z")\
**Posts on this page:** 1\
**Page:** 1

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**Author:** ![Yildiz](https://avatars.discourse-cdn.com/v4/letter/y/df788c/32.png) [@Yildiz](https://gromacs.bioexcel.eu/u/Yildiz)\
**Post date:** [January 22, 2026, 7:46pm UTC](https://gromacs.bioexcel.eu/t/free-energy-verification-by-thermodynamic-integration-in-liquid-solutions/13141/1 "2026-01-22T19:46:49Z")

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GROMACS version: 2025  
Hello all,

I’ve been trying to calculate the activity coefficient of methanol water mixture at specific compositions. I learned how to do TI with Martini but now I have an all-atom system not a coarse-grained model. And I have been having trouble about what methodology to follow, or which mdp file I should use etc. My workflow so far is:

1- Label one of the methanol molecules residue as something else and define it to be the coupled/decoupled molecule.

2- Add that molecule to the topology file

3- Using the same non-bonded interactions add the part about free energy to the mdp file. I am also having trouble about how to select the lambda values, I was recommended 20 states going something like this:  
vdw-lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.10 0.20 0.30 0.40 0.50 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00  
coul-lambdas = 0.00 0.20 0.40 0.60 0.80 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

4- Running a short equilibration and using gmx bar to gather the data.

5- Doing all of these for a pure methanol system to have the reference state data.

Rest is just hand calculation to find activity coefficient. Is this a correct approach? If not, can someone refer me to an article or a tutorial where I can learn the procedure from? I searched for some but couldn’t find any. I’d greatly appreciate all the help.

Best regards,