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

[Jason Zhu]

Dear Justin,

Thank you very much for your prompt response.

It is really a good idea to get the desired structures by "setting the
reference distance to the one you want, setting the pull rate to zero, and
just letting the system equilibrate under the biasing potential". I will
try what you suggest.

Only one small question about the "SMD/PMF" you are referring to in the end
of the letter. Is it the same method (SMD+Umbrella Sampling) I used, or
calculating PMF directly by integrating the force in SMD? I also tried the
latter one. But the result is dependent of the loading rate.

Best,
Wenpeng Zhu

On 4/20/17 2:30 PM, Jason Zhu wrote:
> 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.
>

Force reasonable starting structures by taking the closest snapshot you
have to
the desired distance, set the reference distance to the one you want, set
the
pull rate to zero, and just let the system equilibrate under the biasing
potential.  After a bit of time, you should have a reasonable starting
structure.

> 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?
>

You're unlikely to get good convergence with this approach.  SMD/PMF is the
way
to go.

-Justin