[gmx-users] on the Umbrella Sampling on-line tutorial
chris.neale at utoronto.ca
chris.neale at utoronto.ca
Tue Apr 3 04:26:51 CEST 2012
I'll reply to general topics, not to the tutorial in particular.
If the opening is not large enough to allow the peptide to exit, then
the surrounding protein will need to change its conformation to permit
unbinding. This can happen, but you need (a) to have sufficiently long
sampling times to permit the required conformational change and (b)
starting structures in which the peptide is near the umbrella center
and do not crash during simulation.
The US method is always valid, but it is not always the best choice.
You might try using the free energy code to implement a thermodynamic
cycle. Nevertheless, one imagines that the protein does actually need
to open up during peptide binding and so you will still need to sample
protein opening/closing in order to obtain equilibrium (i.e. correct)
binding free energies because you need to sample the unbound protein
at equilibrium. That is to say that a thermodynamic cycle may appear
converged when in fact it is not, because you have not converged the
unbound state of the protein. In any event, be careful with your
This would be a good system for which to attempt both US and
double-decoupling approaches and use the results of each to ensure
that you are not missing some important conformational states.
That said, I highly doubt that it is possible to converge the free
energies of induced-fit peptide-protein binding with any available
atomistic computational method using contemporary computational
resources. The lower bound of required sampling times is certainly on
the order of 10 us per umbrella and I bet that the actual value is a
few orders of magnitude larger. I have less experience with the free
energy code than I do with US, but I suspect that the required
sampling times are also very long for a system like this.
-- original message --
I planned to use the method introduced in the Umbrella Sampling
on-line tutorial of Justin Lemkul
But if a peptide is surrounded by a protein, which means the opening
of the protein-complex is not large enough to allow the peptide to
leave the protein without significantly breaking the conformation of
the protein in the protein-peptide complex, is the Umbrella Sampling
method still valid for the binding energy calculation?
Will you please also show me in which part of the tutorial the
direction of pull-apart is defined? We should process it in a
direction the peptide can leave the protein, not the direction protein
will bind the peptide much strongly.
I am looking forward to getting a reply from you.
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