Re: [AMBER] Heating the soft core atoms in TI simulations

From: Steinbrecher, Thomas via AMBER <>
Date: Wed, 25 Jan 2023 08:28:05 +0100

Hi Amy,

what does 'not a stable temperature' mean here? It is normal for the
ill-defined temperature of a few atoms to fluctuate wildly, but the (very)
long run average should still be around your target temperature. So if the
SC atoms are at 400 +- 200 K during the simulation, I would not worry much,
if they are at 1K or 10000K, something would indeed be wrong.

There is no theoretical limit for the softcore/transformation region of a
free energy calculation, but your convergence slows drastically once you go
above a handful of atoms. Including a whole sidechain may make sense, but
only if the alchemical change in the side chain will also impact its
preferred conformation. Otherwise, I'd recommend keeping SC regions as
small as you can (Though making it bigger will help make the temperature
look more normal, if nothing else).

Kind Regards,


On Wed, Jan 25, 2023 at 2:01 AM He, Amy via AMBER <> wrote:

> Dear Amber Experts,
> I have a question about Amber TI simulations with soft core potential.
> I want to do a single step morphing and calculate the energy difference of
> changing the charge states of two residues in a protein.
> My system is solvated with explicit waters. There are three soft core
> atoms: The appearing/disappearing H, and two nearby atoms that have
> different types in different charge states. SHAKE is applied to all
> hydrogens except the residues containing these soft core atoms.
> To set up an equilibrated initial structure for the production TI
> simulations, I was trying to minimize, heat and press the initial and the
> end states.
> After running a 50-ps(25000*0.002) heating step: From my MD output, I
> found that the soft core atoms did not achieve a stable temperature of 310K.
> Is it normal for soft core, non-SHAKE atoms to not achieve a stable
> temperature? Or is it because we are calculating the temperature for only 3
> atoms? Or is there anything I did wrong? :”(
> Also, is there an upper limit for the number of soft core atoms? Does it
> make more sense to include the whole residue? Will that drastically
> increase the computing cost?
> Any suggestion would be greatly appreciated. I look forward to learning
> more about TI simulations.
> Many Thanks,
> Amy
> --
> Amy He
> Chemistry Graduate Teaching Assistant
> Hadad Research Group
> Ohio State University
> _______________________________________________
> AMBER mailing list

*Dr. Thomas Steinbrecher*
Principal Scientist CADD
Roche Pharma Research and Early Development
Roche Innovation Center Basel
F. Hoffmann-La Roche Ltd
Bldg. 092/3.92
Grenzacherstrasse 124
4070 Basel
Phone +41 61 682 1319
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Received on Wed Jan 25 2023 - 00:00:03 PST
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