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

Justin Lemkul jalemkul at vt.edu
Sun Nov 16 19:22:08 CET 2014

On 11/16/14 1:04 PM, Oliver Stueker wrote:
> 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.

Why is it necessary to pull only along the z-axis?  For simple ligand binding to 
a globular protein, you can define the pull vector in any or all of the three 
spatial dimensions.  Is there some reason you presuppose binding only along z?

> 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?

It's an additional bias to the Hamiltonian, so it should probably be accounted 
for in some way.  As to how, I'm not sure.  But it's an additional degree of 
freedom that is being restrained.



Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441


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