Hi Dulal,
In the tutorial you are following, it seems they are manually building the endstates and assigning charges. They build the deprotonated state based on the protonated one by changing the charges in tleap. It seems to me the tutorial is saying the VDW is "fortunately set to zero" because then they don't manually have to change the VDW radius from the protonated state. I see how that could be confusing though, because it could seem as if softcore potentials do not handle the VDW parameter. If you want to follow this tutorial, I think you would need to set the VDW for the dummy H in the deprotonated state to be zero using parmed after you have run tleap. Then it will be scaled from the protonated value to zero over the TI simulation.
This sort of pKa simulation is very similar to a relative binding free energy calculation (like in tutorials 7.1 and 7.2) where a ligand is modified, except here a proton is disappearing. If you wanted to leverage some advanced methods from those tutorials, you could consider parameterizing your deprotonated state to obtain a .lib file with consistent atom names for each, building them each in tleap, then using timerge in parmed to generate a dual topology. Hope that helps!
Best regards,
Erika McCarthy
________________________________
From: Dulal Mondal via AMBER <amber.ambermd.org>
Sent: Friday, August 29, 2025 9:38 AM
To: AMBER Mailing List <amber.ambermd.org>
Subject: [AMBER] pKa through TI calculation
Dear Experts,
I am following the tutorial
https://nam02.safelinks.protection.outlook.com/?url=https%3A%2F%2Fambermd.org%2Ftutorials%2Fadvanced%2Ftutorial6%2Findex.php&data=05%7C02%7Cem989%40chem.rutgers.edu%7C17477273cc3d4dd907b008dde7017b46%7Cb92d2b234d35447093ff69aca6632ffe%7C1%7C0%7C638920715734676448%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=JMgk81YuoMisbiwjV7ZdkrLsEE7pLMDSZvMxsXfMrmY%3D&reserved=0<
https://ambermd.org/tutorials/advanced/tutorial6/index.php>
In this tutorial, they describe the Asp residue, for which the VDW terms of
the hydroxyl hydrogen are fortunately set to zero.
I want to calculate the free energy difference between protonated Lys and
deprotonated Lys. However, for the hydrogens bound to nitrogen, the VDW
parameters are *not zero*. Should I explicitly modify the VDW parameters in
the deprotonated Lys prmtop file?
--
*With regards,*
*Dulal Mondal,*
*Research Scholar,*
*Department of Chemistry,*
*IIT Kharagpur, Kharagpur 721302.*
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Received on Fri Aug 29 2025 - 12:00:02 PDT
