[gmx-users] on the Umbrella Sampling on-line tutorial

[chris.neale at utoronto.ca]

Dear Acoot:

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  
convergence analysis.

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.

Chris.

-- original message --

Dear All,

I planned to use the method introduced in the Umbrella Sampling  
on-line tutorial of Justin Lemkul  
(http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html).

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.

Cheers,

Acoot