Re: AMBER: Potential of mean force, how to calculate rate of dissociation?

From: David Mobley <>
Date: Fri, 4 May 2007 14:09:36 -0700


> thanks for pointing this out David, I fully agree that what I said is only
> true in the limit of full equilibration, which is hard enough to achieve
> for a single bound ligand conformation and quite possibly impossible for
> many dissociation processes. I guess one can sum it up that PMF's give you
> an upper bound of the activation free energy that may be a very bad
> estimate but should converge to the true one in the limit of infinite
> sampling. Since the rate would depend exponentially on E(activation),
> calculated rates would be even less reliable.

Again, it depends on the reaction coordinate you pick. It's possible
to pick a reaction coordinate such that you would never get the right
activation energy regardless of how long you ran. I suppose if you
simply pull radially, in the infinite-sampling limit, you would
eventually find the "most relevant" pathways out and average over
those sufficiently. But in most applications radial pulling is
probably more expensive than pulling in a particular direction with
respect to the protein (since radial pulling involves sampling
everywhere over a spherical shell at each r for convergence). And
pulling in a specific direction, even in the infinite-sampling limit,
should just give you the activation barrier along that specific

But, as you note, it's true that these are an upper bound (assuming
the force field is adequate) on the true activation barrier, so maybe
they could still be useful.

Best wishes,

> Regards,
> Thomas
> Dr. Thomas Steinbrecher
> The Scripps Research Institute
> 10550 N. Torrey Pines Rd.
> San Diego CA 92037, USA
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Received on Sun May 06 2007 - 06:07:33 PDT
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