Re: TI alchemical transformation of a ring atom: small partial charge difference affects strongly dG

From: Peter Freddolino (
Date: Sun Jul 19 2020 - 20:54:13 CDT

Dear Mateusz,
Unfortunately because your posted file is a mol2 file without any
specification of incoming/outgoing atoms (and your imgur link leads to a
blank page), it is difficult to figure out exactly what is going on here.
Could you begin by giving a clearer description of the various ways that
you've attempted to run this, and the results that you got? Where do you
derive your expectation from? Why isn't just the single atom Cl->Br
perturbation the right way to go? Do the parameters for anything else in
the ring have to change? Dealing properly with the bond and angle terms in
a ring system during decoupling is tricky business. Could you also check
and confirm that the net charge of the incoming/outgoing groups is equal in
each case?

On Sat, Jul 18, 2020 at 11:39 AM Mateusz Bieniek <>

> Hi everyone,
> I am transforming a ring into the same ring by mutating only one atom.
> That's the C7 ring here
> Mutating just the sticking out heavy atom Cl/Br works fine and so far is
> the only way for me to obtain correct energies.
> One of the atoms has a slightly different charge, and I need to mutate it
> (it is an automated protocol). The small charge difference is 0.12e.
> However, that mutation leads to very large dG in the electrostatic
> component (3.5 kcal/mol, reproducible). When I match the charge on the
> incoming and outgoing ring atom, the problem disappears. If I reduce the
> charge, the dG electrostatic integral decreases substantially.
> I have so far used only the dual topology approach in NAMD. However, I am
> surprised that such a small change in the charge leads to dG blowing up. I
> expect the ring to be solid because I do not degrade the bonds during the
> transformation. Therefore, the atom should remain in the same position.
> Furthermore, this atom should have the same position with respect to the
> ring.
> I added a rather naive test where I set scaling14 to 0.2 value. This has
> dramatically reduced the 3.5 kcal/mol to 1.5 kcal/mol. Although it is
> tricky to conclude anything. Nevertheless, the ring atom C7 transformation
> introduces a huge change in the electrostatic component, but I cannot see
> how C7 could interact with anything, and how such small changes in the
> partial charge could change dG so much.
> The combined molecule:
> Many thanks,
> Mateusz Bieniek

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