Re: ABF (fwd)

From: Matthew Davies (
Date: Tue Nov 14 2006 - 10:10:38 CST

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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