From: Jerome Henin (jhenin_at_cmm.chem.upenn.edu)
Date: Tue Nov 14 2006 - 18:52:10 CST
I think the method of choice would probably be alchemical FEP.
Relative free energies of binding can sometimes be obtained with limited pain.
An recent example using NAMD is Henin et al., Biophysical Journal
90:1232-1240 (2006) - sorry for the self-promotion... there are many more
examples, but I can't seem to remember them right now :-)
"Absolute" binding free energies are trickier. The most interesting work I
know of in that field is that of the Roux group - see e.g. Wang et al.,
Biophysical Journal 91:2798-2814 (2006).
On Tuesday 14 November 2006 11:10, Matthew Davies wrote:
> Dear Jerome
> Thank you for your prompt reply. What we are trying to do is calculate the
> ease of dissociation of one peptide compared to another. We would predict
> that in cases of weak binding it would be easier for the complex to
> undergo disassociation due to the absense of stabilising interactions
> with the receptor. The dissociative pathway itself is of less interest.
> Given that information, which of the techniques that you mentioned would
> you recommend we use?
> Best wishes and many thanks
> On Tue, 14 Nov 2006, Jerome Henin wrote:
> > Dear Matthew,
> > I'm afraid the case you are studying is far from easy to tackle using
> > ABF, for two reasons: ABF is about reversibility, and the NAMD
> > implementation is one-dimensional (for now).
> > The dissociation of a receptor-peptide complex is very hard to describe
> > by a single geometric parameter, and it is even harder to simulate that
> > process reversibly: is the association likely to be observed over MD
> > timescales? Actually the two problems are very much linked: if all
> > relevant geometric parameters could be properly accounted for and biased,
> > then reversible association and dissociation would be more easily
> > observed.
> > The question is: what information do you want to obtain? Is it really the
> > PMF? Is it a qualitative description of the process? Is is the free
> > energy of binding? In the latter case, computing a PMF is probably not
> > the way to go. A lot of work has been done in that field, e.g. using FEP
> > with or without restraining potentials. I can give you specific
> > references if you don't have them.
> > For a qualitative description, SMD (pulling as slowly as you can afford!)
> > may be easier to control than ABF.
> > There is a second ABF-related issue, not that important though: in your
> > simulations, some non-equilibrium pulling seems to have happened. That
> > kind of undesirable effect can be avoided by using high values of the
> > fullSamples parameters - the slower the system is, the higher it should
> > be.
> > Best,
> > Jerome
> > On Tuesday 14 November 2006 08:40, Matthew Davies wrote:
> > > Dear fellow NAMD users
> > >
> > > We are trying to implement the ABF technique to study the dissociation
> > > of a receptor-peptide complex. The receptor binds a single
> > > peptide of 12 amino acids in length. We have applied the technique
> > > by defining the peptide as one centroid and the binding groove of the
> > > receptor as the other centroid and in the simulation we have observed a
> > > clear dissociation of the peptide from the receptor.
> > >
> > > Our problem has been in the calculation of the A(xi) values for the
> > > simulation, specifically in selecting the values of xiMin and xiMax
> > > values. At the initial point of our simulation, the two centroids are
> > > approximately 10.4A apart. When we sample the A(xi) values between
> > > 10-20A and 15-20A, we get singificantly higher values for the former.
> > > We are confused by this as we had thought the initial and final points
> > > of sampling would not significantly affect the determined values. Can
> > > you suggest at to why this might occur? I have attached both .dat files
> > > as examples.
> > >
> > > Best wishes
> > >
> > > Matthew Davies
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