[gmx-users] Open-closed transition in a dimeric enzyme, WTM simulations

[Erik Marklund]

Dear Tarak,

My guess is that your reaction coordinate is ill-chosen and that it fails to capture some significant transitions in orthogonal directions. This can be difficult to know beforehand unfortunately.

Kind regards,
Erik

> On 10 Jun 2016, at 19:09, tarak karmakar <tarak20489 at gmail.com> wrote:
> 
> Dear All,
> I am studying an enzyme where the closing of a loop should happen upon
> ligand binding to the active site. In unbiased simulations, even after 300
> ns of simulation time the loop does not close the reaction center. Thus, we
> realized that the open-closed conformational change may have a high free
> energy barrier, inaccessible by the unbiased trajectory. Thus, we performed
> well-tempered metadynamics (WTM) simulations to study that event.
> 
> In WTM simulations, we see the opening and closing of the loop almost five
> to six times within 300 ns time span. The free energy associated with this
> event has barriers of only few kJ/mol (almost flat surface). Now, given
> these low values of the free energy barriers, I would expect to observe the
> open-closed transitions in the unbiased simulations. However, we do not see
> that transition in the unbiased trajectories.
> 
> So, my questions are,
> 1) Are the collective variables used here inappropriate? (Although I see
> the open-closed
> transition a many times in the metadynamics trajectory.)
> 
> 2) Is the free energy not converged? (plotting hills heights a function of
> time, decays close to zero after 200-250 ns)
> 
> 3) How would I make sure that the free energy is converged? (block averages
> using -stride in plumed) How would I decide the blocks from the COLVAR plot?
> 
> Any suggestions would be highly appreciated.
> 
> -- 
> Regards,
> Tarak
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