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From: David Mobley <dmobley.gmail.com>

Date: Fri, 4 May 2007 10:39:34 -0700

Thomas,

*> I haven't much experience with US and WHAM analysis, but the way I always
*

*> thought about
*

*> it was that the PMF is a very nice thing because it gives you not only a
*

*> free energy difference between two endstates (the binding constant) but
*

*> also the maximum of the free energy curve between them and thus the
*

*> activation free energy for the process. From that you could easily
*

*> calculate the back and forth rates and even look at the conformations at
*

*> the maximum that pose the critical chokepoint for dissociation.
*

*> Someone please correct me if I'm wrong,
*

That, of course, depends on having picked the "right" reaction

coordinate for calculating the PMF along (if there is any single

"right" reaction coordinate). In practice this is probably essentially

impossible for biomolecules, since (a) association and dissociation

probably involved coupled motions of protein and ligand, and forcing

calculation along that reaction path would be very difficult, and (b)

there may be many different microscropic paths relevant for

association/dissociation, just as there can be many different paths

relevant for protein folding; the observed rate for

association/dissociation, like a protein folding rate, reflects some

kind of an average over microscopic paths.

Of course, from a PMF, you can calculate a reaction rate based on the

barrier heights, as you suggest. I just think the above considerations

mean that it shouldn't necessarily be expected to be meaningful.

Just one example: Suppose I calculate the PMF for removing a ligand

from a protein, along some particular vector V away from the protein,

and I've carefully picked this vector so the ligand encounters few

steric obstructions along the way. And then I do a second calculation

where I pull it along another vector, W, that is based on just a quick

inspection of the crystal structure to give me a rough idea of a

reasonable direction.If I converge the calculations, the two should

give me the same binding free energy, but will have different barrier

heights along the way, and hence give different rates.

David

*> Kind Regards,
*

*>
*

*> Thomas
*

*>
*

*> Dr. Thomas Steinbrecher
*

*> The Scripps Research Institute
*

*> 10550 N. Torrey Pines Rd.
*

*> San Diego CA 92037, USA
*

*> -----------------------------------------------------------------------
*

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*

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*

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*

*>
*

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Received on Sun May 06 2007 - 06:07:31 PDT

Date: Fri, 4 May 2007 10:39:34 -0700

Thomas,

That, of course, depends on having picked the "right" reaction

coordinate for calculating the PMF along (if there is any single

"right" reaction coordinate). In practice this is probably essentially

impossible for biomolecules, since (a) association and dissociation

probably involved coupled motions of protein and ligand, and forcing

calculation along that reaction path would be very difficult, and (b)

there may be many different microscropic paths relevant for

association/dissociation, just as there can be many different paths

relevant for protein folding; the observed rate for

association/dissociation, like a protein folding rate, reflects some

kind of an average over microscopic paths.

Of course, from a PMF, you can calculate a reaction rate based on the

barrier heights, as you suggest. I just think the above considerations

mean that it shouldn't necessarily be expected to be meaningful.

Just one example: Suppose I calculate the PMF for removing a ligand

from a protein, along some particular vector V away from the protein,

and I've carefully picked this vector so the ligand encounters few

steric obstructions along the way. And then I do a second calculation

where I pull it along another vector, W, that is based on just a quick

inspection of the crystal structure to give me a rough idea of a

reasonable direction.If I converge the calculations, the two should

give me the same binding free energy, but will have different barrier

heights along the way, and hence give different rates.

David

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Received on Sun May 06 2007 - 06:07:31 PDT

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