[gmx-users] Non-overlapping region appears in histograms when using SMD+Umbrella Sampling for strong binding complex

[Jason Zhu]

Dear All,

I am modeling the binding free energy between a molecule of sodium cholate
and a 2D nanosheet by using steered MD and umbrella sampling as guided by
Gromacs Tutorial 3 (
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html
).

The small molecule has a strong binding with the surface of nanosheet. I
first performed a Steered MD to pull the molecule away from the surface.
The loading rate is low as 0.01 nm/ns, the force constant for pulling is
1000 kJ/nm2 and the output frequency of configuration is 1 frame very 100
ps.

However, due to the strong binding, the COM distance between the molecule
and nanosheet has a big jump (~0.4 nm) at the detachment. I cannot extract
successive sufficiently configurations at the moment of detachment for
umbrella sampling (10 ns sampling). Even if I choose every configurations
near the detachment for sampling, the histograms still have a wide gap and
the curve in the energy profile is noncontinuous.

I have tried to increase the force constant for pulling and even decreased
the loading rate. But the problem still exists.

I wonder if you have any experience to solve this problem. It would be
appreciated if you could provide any suggestion.

Should I use the other method for free energy calculation as in the Gromacs
Tutorial 6 (
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/index.htm),
instead of using SMD and umbrella sampling? But there are also some
questions when I use this method. First, the molecule is negatively
charged. When I uncouple the electrostatic interactions, should I uncouple
the sodium ions? If so, I am calculating the free energy of the molecule
and its neutralizing ion, not only the molecule. Is it correct? If I am
only interested in the molecule, what should I do? In this method, unlike
the umbrella sampling, we only can get the free energy change, not the
energy curve that includes the information of energy barrier. Is it correct?

Many thanks for your helps in advance!

Best,
Wenpeng Zhu