Re: [AMBER] PMF problem

From: Daniel Sindhikara <>
Date: Wed, 2 Feb 2011 11:49:33 +0900

Not sure if I understand your situation but it seems you are trying to
interpret the
difference between a 2d and 1d FES? You call the 1D a "quasi-1D" because you
integrated over the 2nd dimension, but the 2D surface integrates over all
other dimensions.
If your 1D shows a minimum at one end and the 2D shows it at the other end
on the same axis, then the discrepancy is clearly entropy.
In terms of your coordinates, RC1=10,RC2=1 is the lowest free energy,
but there are many low free energy points at RC1=1, which is why the
integral over RC2 shows this to be a minimum.

This is all assuming that your calculations were correct, and that your
umbrella sampling simulations were well converged, and your force-field
accurate (a big heap of assumptions).

If this result is contrary to what you expect, may I suggest you recheck
your simulation parameters.


On Wed, Feb 2, 2011 at 5:55 AM, dhacademic <> wrote:

> Hi everyone,
> I have a problem in 2D PMF calculations.
> There are two reaction coordinates (RC) in my system. RC1 stands for
> conformational change of protein (RC1 ranges from 1 to 10, where RC1=1
> means
> closed state of protein, RC1=10 means open state), and RC2 is the distance
> between ligand and active site (RC2 ranges from 1 to 10, where RC2=1 means
> ligand bound state, RC2=10 means ligand escaped state). After the
> time-consuming umbrella sampling calculations (with amber9) on two RCs, the
> 2D free energy profile can be obtained with WHAM program. However, the open
> state of protein with ligand bound to active site (RC1=10, RC2=1) is found
> to be a minimum on the free energy surface, while the closed state with
> ligand bound has higher energy (RC1=1, RC2=1). This is opposite to what I
> have expected, where the closed state of protein with ligand bound should
> be
> a stable state.
> Then the umbrella sampling data of different RC1 (from 1 to 10) with fixed
> RC2 (RC2=1) are used to get quasi-1D free energy profile of protein
> conformational change with ligand bound, and the results seem to be
> reasonable: the open state is energetic unfavorable, and the closed state
> has a minimum. The system stability in quasi-1D free energy profile is
> reasonable.
> Besides, umbrella sampling on RC1 (no bias potential is imposed on RC2, and
> the ligand position and orientation is almost unchanged because there are
> lots of favorable interactions between ligand and active site is strong)
> was
> done on the same system. The generated 1D-PMF results is quite similar to
> the quasi-1D one, and quite different to the 2D-PMF results when RC2=1.
> All the structures as well as the data have been carefully checked.
> Everything looks good, but the results look strange. I do not understand
> why
> the stability of the system in 2D-PMF and quasi-1D-PMF is different. As the
> results from 2D-PMF are inconsistent with common knowledge of
> protein-ligand
> complex, I think there may be something wrong with my 2D-PMF calculations.
> Can anyone give some suggestions? Thanks in advance!
> Best,
> Hao
> _______________________________________________
> AMBER mailing list

Dr. Daniel J. Sindhikara
Institute for Molecular Science
AMBER mailing list
Received on Tue Feb 01 2011 - 19:00:04 PST
Custom Search