# Re: [AMBER] PMF problem

Date: Wed, 2 Feb 2011 10:40:26 -0500

Thanks for the reply. Let me make it more clear.

I have one FE-surface and two FE-profiles:
(a) 2D-FES (umbrella sampling with both RC1 and RC2);
(b) quasi-1D-FE-profile (PMF calculation with varied RC1 and fixed RC2 (for
example, RC2=1). So the result is not integrated over the RC2. In reality,
it should be a thin slice of 2D-results);
(c) 1D-FES (umbrella sampling only with RC1).

Results from (b) and (c) are consistent. (b) and (a) are inconsistent, which
makes me confused. I can understand that 2D-FES may differ to "quasi-1D"
FE-profile because of the integral over RC2 dimension. But in present case,
my quasi-1D FE-profile is only one slice of 2D-FE-surface, which should not
change the location of minimum.

I will check the parameters as well as simulations again. But any other
suggestion is appreciated!

Best,
Hao

On Tue, Feb 1, 2011 at 9:49 PM, Daniel Sindhikara <sindhikara.gmail.com>wrote:

> 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.
>
>
> --Dan
>
> On Wed, Feb 2, 2011 at 5:55 AM, dhacademic <dhacademic.gmail.com> 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
> > AMBER.ambermd.org
> > http://lists.ambermd.org/mailman/listinfo/amber
> >
>
>
>
> --
> Dr. Daniel J. Sindhikara
> Institute for Molecular Science
> E-mail: sindhikara.gmail.com