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

From: Mateusz Bieniek (bieniekmat_at_gmail.com)
Date: Sat Jul 18 2020 - 09:30:33 CDT

Hi everyone,

I am transforming a ring into the same ring by mutating only one atom.
That's the C7 ring here https://imgur.com/1vSkZ8k

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

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

This archive was generated by hypermail 2.1.6 : Thu Dec 31 2020 - 23:17:13 CST