Re: Question on making 'reversible' solvated simulation

From: Brian Radak (brian.radak_at_gmail.com)
Date: Mon Feb 19 2018 - 11:00:20 CST

I've never dealt with displacing water molecules before. In addition to the
trickiness of the chemical potential of water, choosing your restraints
would likely be really tricky. You could also "displace" the water
molecules alchemically by having them on top of the ligand in one endpoint
and then move them into the bulk at the other, but you'd still have to no
exactly how many water molecules you are talking about (maybe try multiple
counts?).

This might also muck up performance a bit because the alchemical region is
spread out, but it would simulate the bound/bulk transition explicitly.

On Sat, Feb 17, 2018 at 12:20 PM, Randy J. Zauhar <r.zauhar_at_usciences.edu>
wrote:

> Hi Brian,
>
> Is there any reason this would not work acceptably?
>
> 1) Equilibrate apo protein in solvent, active site is restrained in
> ligand-bound conformation
>
> 2) At end of equilibration, identify waters in active site by overlap with
> ligand atoms when bound.
>
> 3) Restrain active site water positions and re-equiibrate
>
> 4) Annihilate waters while creating ligand, and vice-versa to check
> reversibility. If I am correct I just need a merged PSF with both active
> site waters and ligand, and tag one group for creation, the other for
> annihilation.
>
> I have not thought about the actual thermodynamic cycle that implies -
> Probably would need to do the same thing in bulk solvent (i.e. extract the
> active site waters and solvate them in a box as part of the
> annihilation/creation of ligand in bulk) ??
>
> Thanks!
>
> Randy
>
>
> On 12Feb, 2018, at 11:00 AM, Brian Radak <brian.radak_at_gmail.com<mailto:
> brian.radak_at_gmail.com>> wrote:
>
> A rather involved, but essentially equivalent route that could be pursued
> in NAMD is to apply an orthogonal bias (or series of biases) on the water
> molecules. The bias energy could then be removed in a reweighting step
> (this goes beyond the normal procedure implemented in ParseFEP, for
> example, so you should probably be comfortable writing your own WHAM code
> in order to attempt this).
>
> I've never tried this, but I believe it could be implemented with boundary
> forces (tclBC)? You might profitably reduce the overall number of
> simulations by using an adaptive method like ABF or metadynamics to get a
> global bias (as opposed to a local bias like a harmonic restraint). Again,
> this is really complicated.
>
> Accelerated MD (or Gaussian accelerated MD) or even simulated tempering
> might also work. We're actively trying to couple alchemical calculations
> with REST2 for essentially this purpose, but that will not be released
> until NAMD2.14 at the earliest (yes, that far ahead).
>
> HTH,
> Brian
>
>
> On Sun, Feb 11, 2018 at 1:52 PM, Randy J. Zauhar <r.zauhar_at_usciences.edu<
> mailto:r.zauhar_at_usciences.edu>> wrote:
> Jerome, thanks - I see the issue of site de-solvation not being properly
> included. ;-(
>
> One thing I will check is my protein preparation - it is possible that I
> removed crystallographic active site waters, and the ones that crept in are
> in fact occupying similar positions. In that case I could simply include
> the xtal waters. That would at least improve things.
>
> Another would be to retain the ‘solvent wall’, and introduce some active
> site waters in place of the ligand. Could then do a separate simulation to
> annihilate the active site waters, which would also provide some measure of
> de-solvation by the ligand.
>
> Ultimately we want to compare ligands for the same target, and the
> desolvation of the site should be similar for each.
>
> Randy
>
> P.S. I will take a look at the work by Yang, but do not contemplate moving
> to CHARMm over this!
>
> On 11Feb, 2018, at 5:56 AM, Jérôme Hénin <jerome.henin_at_ibpc.fr<mailto:j
> erome.henin_at_ibpc.fr><mailto:jerome.henin_at_ibpc.fr<mailto:jero
> me.henin_at_ibpc.fr>>> wrote:
>
> Hi Randy,
>
> While adding a barrier to entry for water molecules may well make the
> simulation more reversible, it will also make it biased and give an
> overestimated binding affinity, by killing the binding site desolvation
> contribution.
>
> It's a tough problem, but ideally this solvation/desolvation process needs
> to be sampled.
>
> Improving the sampling of that kind of "orthogonal" process was the focus
> of some work by Wei Yang:
> http://www.pnas.org/content/105/51/20227.full
> https://pubs.acs.org/doi/abs/10.1021/ct200726v
>
> But that's only implemented in CHARMM afaik. The theory is somewhat
> involved.
>
> So I'm sorry to say, if it's a common problem, there is no universal,
> simple and consensual approach to it.
>
> Best,
> Jerome
>
>
> On 10 February 2018 at 19:15, Randy J. Zauhar <r.zauhar_at_usciences.edu<
> mailto:r.zauhar_at_usciences.edu><mailto:r.zauhar_at_usciences.edu<mailto:
> r.zauhar_at_usciences.edu>>> wrote:
> Hi,
>
> I am running a ligand annihilation in a solvated system, and I would like
> to make it truly reversible if possible.
>
> Issue is that a couple water molecules sneak into the active site when the
> ligand disappears. Then when I reverse and start creating the ligand, they
> are trapped.
>
> A simple thing I will try is to constraint the water molecules close to
> the active site, hopefully creating a barrier to entrance.
>
> However. this has to be a pretty common problem, is there a recommended
> approach to address it?
>
> Thanks!
> Randy
>
> Randy J. Zauhar, PhD
>
> Prof. of Biochemistry
>
> Dept. of Chemistry & Biochemistry
> University of the Sciences in Philadelphia
> 600 S. 43rd Street
> Philadelphia, PA 19104
>
> Phone: (215)596-8691<tel:%28215%29596-8691>
> FAX: (215)596-8543<tel:%28215%29596-8543>
> E-mail: r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu><mailto:
> r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu>><mailto:
> r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu><mailto:r.zauhar@
> usciences.edu<mailto:r.zauhar_at_usciences.edu>>>
>
>
>
> “Yeah the night is gonna fall, and the vultures will surround you /
> And when you’re lookin’ in the mirror what you see is gon’ astound you"
>
> — Death Cab for Cutie, “Monday Morning"
>
>
>
>
>
>
> Randy J. Zauhar, PhD
>
> Prof. of Biochemistry
>
> Dept. of Chemistry & Biochemistry
> University of the Sciences in Philadelphia
> 600 S. 43rd Street
> Philadelphia, PA 19104
>
> Phone: (215)596-8691<tel:%28215%29596-8691>
> FAX: (215)596-8543<tel:%28215%29596-8543>
> E-mail: r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu><mailto:
> r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu>>
>
>
>
> “Yeah the night is gonna fall, and the vultures will surround you /
> And when you’re lookin’ in the mirror what you see is gon’ astound you"
>
> — Death Cab for Cutie, “Monday Morning"
>
>
>
>
>
>
> Randy J. Zauhar, PhD
>
> Prof. of Biochemistry
>
> Dept. of Chemistry & Biochemistry
> University of the Sciences in Philadelphia
> 600 S. 43rd Street
> Philadelphia, PA 19104
>
> Phone: (215)596-8691
> FAX: (215)596-8543
> E-mail: r.zauhar_at_usciences.edu<mailto:r.zauhar_at_usciences.edu>
>
>
>
> “Yeah the night is gonna fall, and the vultures will surround you /
> And when you’re lookin’ in the mirror what you see is gon’ astound you"
>
> — Death Cab for Cutie, “Monday Morning"
>
>
>
>

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