PMX alchemical free energy calculation for protein mutation

pmx
1

I am trying to reproduce the results ΔΔG of protein mutation (W6F), that you have provided in Protein mutation — pmx documentation. I have used devlop branch of pmx for alchemical calculation. I am using the parameters files that you have shared to the site for foward and reverse calculation. I have executed all the commands in Linux terminal and gromacs 2023.5 is installed in my system. I have equlibrated systems for 5 ns. Total, 50 equidistant frames were used to run non-equlibrium simulation.

For protein.pdb for W2F mutation at 6 position, WT→Mut (state A) & Mut→WT (State B), I am getting average ΔG=−3.64±0.85 kJ/mol of 5 replicas, which is far away from the value 9.75±1.48 kJ/mol that you have mentioned.

For tripeptide, W2F mutation at 3 position, WT→Mut (state A) & Mut→WT (State B), I am getting average ΔG=−17.29±0.27 kJ/mol of 5 replicas, which is again far away from the value −4.82±0.19 kJ/mol that you have mentioned.

In my case, ΔΔG=(−3.64±0.85)−(−17.29±0.27)=13.65±0.89.
in your site, ΔΔG=(9.75±1.48 )−(−4.82±0.19)=14.57±1.49.
same FF was used (amber99sb-star-ildn-mut).

Plz provide solution, how to get similar results for folding and unfolding cases.

2

Hi,

The ‘develop’ branch of pmx uses a different atom mapping than that of the tutorial. Therefore, the dG estimates from individual branches (folded and unfolded) are not expected to match with the one from the tutorial.

However, the ddG (unfolded-folded) should be reproducible, which is very much the case in your simulations. Further, ddG is the relevant observable and can be directly compared with the experiment.

Overall, your results are fine.

All the best,
Sudarshan