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From: Jason Swails <jason.swails.gmail.com>

Date: Wed, 28 Jan 2015 17:25:02 -0500

*> On Jan 28, 2015, at 3:52 PM, hannes.loeffler.stfc.ac.uk wrote:
*

*>
*

*> Well, my definition is essentially what you say about being mathematically identical that is the user can swap both codes and expect the "same" result (ignoring for the moment the different setup and the fact that sander can't do the lambda end states).
*

*>
*

*> Of course, pmemd does dual-topology, as well as single-topology (in effect at least) for direct conversion of atoms through linear scaling. So it is a hybrid. The elimination of terms for pmemd is actually an artefact of the setup with leap. But that's because you may explicitly need to copy all or part of your system to get leap do the right thing (proteins). If you do (non-covalently bound) ligands you don't need this step obviously.
*

Agreed.

*> I don't quite understand your second paragraph about computing the averages.
*

H = lambda*H1 + (1-lambda)*H2 <-- H is effectively a lambda-weighted average of the two end-point Hamiltonians (at least in this flavor of TI, which is the one implemented in Amber). The naive, easy way to do this is compute H1 and H2 separately and then combine the energies and forces in that lambda-weighted average. This is what sander does, and it hijacks multisander to do it.

For the terms that don’t depend explicitly on lambda (and by extension don’t contribute to dV/dl), sander still computes them in both states and averages them. By contrast, pmemd computes the lambda-independent parts only once and averages the lambda-dependent parts. This results in a nice speedup for PME by roughly halving the expensive direct-space sum (but not much for GB given that the most expensive part is almost entirely lambda-dependent).

*> I am not sure if there is currently sufficient evidence to say that MBAR is more efficient than TI or vice versa.
*

Well I think it’s pretty clear that MBAR with TI is more efficient (in its worst case, it is just as efficient). Especially since all of the MBAR energies can be computed with virtually no cost by sander and pmemd, I think the only real barrier to incorporating MBAR as a routine part of every TI calculation is the lack of mature tools that automate it.

As for a non-TI method using MBAR to compute energies, I’d be skeptical of claims that TI is worse...

All the best,

Jason

Date: Wed, 28 Jan 2015 17:25:02 -0500

Agreed.

H = lambda*H1 + (1-lambda)*H2 <-- H is effectively a lambda-weighted average of the two end-point Hamiltonians (at least in this flavor of TI, which is the one implemented in Amber). The naive, easy way to do this is compute H1 and H2 separately and then combine the energies and forces in that lambda-weighted average. This is what sander does, and it hijacks multisander to do it.

For the terms that don’t depend explicitly on lambda (and by extension don’t contribute to dV/dl), sander still computes them in both states and averages them. By contrast, pmemd computes the lambda-independent parts only once and averages the lambda-dependent parts. This results in a nice speedup for PME by roughly halving the expensive direct-space sum (but not much for GB given that the most expensive part is almost entirely lambda-dependent).

Well I think it’s pretty clear that MBAR with TI is more efficient (in its worst case, it is just as efficient). Especially since all of the MBAR energies can be computed with virtually no cost by sander and pmemd, I think the only real barrier to incorporating MBAR as a routine part of every TI calculation is the lack of mature tools that automate it.

As for a non-TI method using MBAR to compute energies, I’d be skeptical of claims that TI is worse...

All the best,

Jason

-- Jason M. Swails BioMaPS, Rutgers University Postdoctoral Researcher _______________________________________________ AMBER mailing list AMBER.ambermd.org http://lists.ambermd.org/mailman/listinfo/amberReceived on Wed Jan 28 2015 - 14:30:02 PST

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