[gmx-users] Umbrella Sampling and flat-bottom position restraints

[Oliver Stueker]

Dear fellow Gromacs Users,

I'm trying to calculate the binding free energy between a protein and a
small molecule using Umbrella Sampling.

I made my first attempt last year using Gromacs 4.5 and ran into the same
convergence problems that have been pointed out on the mailing list several
times.
To overcome these problems I now want to give it another try utilizing the
flat-bottomed position restraints that have been introduced in Gromacs 5.0.

My plan is to perform the Umbrella sampling along the Z-axis and to
restrict the protein as well as the ligand with flat-bottomed position
restraints along X and Y into a cylindrical space (as suggested e.g. by
Chris Neale in [1]).

But I'm not quite sure what radius the cylinder should have ( or how wide
the flat bottom should be).
The protein is roughly spherical with a diameter of ~4nm. I was initially
thinking to use an r_{fb} of 2nm for the protein and  for the ligand 1/2 of
it's longest dimension to allow both of them to re-orient freely. But the
more I think about, I'm afraid that it's too large.

Has anyone have experience with that? Maybe even a published paper?
So far I've unsuccessfully tried several times to find a published method.


Also to I need to consider the flat-bottomed potential when doing the
g_wham analysis?


Thanks,
Oliver


[1]
https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2014-March/087644.html