I have been experimenting a little bit with the AWH feature (thanks to the developers) for the purpose of obtaining PMFs for passage of a fairly large molecule (not too big I think, a cyclic peptidomimetic about the same size as 5-6 residues) and wonder what possible reasons for
A) not obtaining a symmetric PMF, and
B) the PMF is also very “rugged”. Even though the overall shape makes sense, there are multiple bumps on the order of 1-2 kj/mol that I would like to get rid of. These are especially pronounced in the region of the PMF that corresponds to the bilayer interior.
Many thanks for your reply. We did not really do any careful analysis of how long to run, it was mostly based on how much resources were available. Current runs are up to 700 ns each, and with most settings following the ones specificed in the “Refined Predictions of Skin Permeability Using Molecular Dynamics Simulation and the Accelerated Weight Histogram Method”-paper.
Couple-intramol was set to no, but not sure about this one for a somewhat large-ish molecule?
You didn’t write this explicitly, but if you are computing passage and talking about coupling, do I understand correctly that you are applying AWH in 2D: both a physical reaction coordinate and lambda coupling?
That is a very challenging calculation.
I would think that couple-intramol=yes would be more efficient for such a large molecule. You can check yourself if there are significant conformational changes between the coupled and decoupled states.
Hm, I feel I am missing something fundamental here, but essentially what you are saying is that typically with AWH, you do not need to specify anything pertaining to the “normal” free energy options? My intent was to run a 1-D AWH to get the PMF for translocation across a bilayer?
If you are running a 1-D AWH with the pull code, you don’t have a free-energy coupling lambda and couple-intramol (and all other lambda parameters) is irrelevant.