Re: [AMBER] Any one reported a drug dissociation barrier could be as high as 100 kcal/mol ?

From: Jason Swails <>
Date: Mon, 20 Dec 2010 00:36:03 -0500


It is very important in this case to distinguish between thermodynamics and
kinetics. If Cat is talking about a barrier height, then Kds really don't
play into this (since that's typically assumed to be an equilibrium constant
which is independent of barrier heights).

Using transition state theory, you can get quick orders-of-magnitude
estimates for what the barrier height should be in order to have a
first-order half-life of 1 minute, and my guess would be that it's
considerably less than 100 kcal/mol.

If large conformational changes are present upon binding/unbinding, then
this becomes a very, very difficult calculation since the PMF has to take
into account this global relaxation, which is on average a very slow
process. My guess would be that you are not sampling the actual path and/or
your PMF is not nearly converged due to these slow global motions.

Another important check is that the endpoints of your PMF do in fact match
the experimental delta G of binding if there is one.

Hope this helps,

On Sun, Dec 19, 2010 at 1:53 PM, Dmitry Mukha <> wrote:

> 2010/12/19 Catein Catherine <>
> >
> > Did any one read any publication reported that the potential of mean
> force
> > for a drug dissociation from its receptor could be as high as 100
> kcal/mol?
> >
> >
> The most tight non-covalent complexes reported are avidin/streptavidin and
> barnase/barstar (and some other rnase with rnase inhibitor). Kd of these
> complexes lie below femtomol/liter order, which is equivalent to free
> energy
> slightly below -20 kcal/mol. Free energy near 100 kcal/mol corresponds to
> the Kd ~10E-73 M. How to measure this huge energy value? Maybe by
> calorimetry technique?
> --
> Sincerely,
> Dmitry Mukha
> Institute of Bioorganic Chemistry, NAS, Minsk, Belarus
> _______________________________________________
> AMBER mailing list

Jason M. Swails
Quantum Theory Project,
University of Florida
Ph.D. Graduate Student
AMBER mailing list
Received on Sun Dec 19 2010 - 22:00:04 PST
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