this is discussed in the manual on page 546 under "27.1. Distance, angle
and torsional restraints"
https://ambermd.org/doc12/Amber20.pdf
On Wed, Jul 15, 2020 at 5:50 PM Debarati DasGupta <
debarati_dasgupta.hotmail.com> wrote:
>
> Dear Amber users
>
> I found a paper on absolute free energy methods referenced
> https://doi.org/10.1016/j.jmb.2009.09.049
>
> In the Supplementary info section, I found this paragraph. I am trying to
> understand two things (1)how to implement angle, torsional restraints in
> AMBER18.
> Also the last line of the paragraph says “To prevent large
> forces...exceeds the distance by 0.2 nM with the slope...” (2) how do we
> fine tune the ntr=1 such that our distance restraint can be linearly
> increased based on how far the ligand scoots out of the receptor pocket?
> Anyone can help?
> Thanks
> Regards
>
>
> [cid:image001.png.01D65ACF.7EDD49D0]
>
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> From: Debarati DasGupta<mailto:debarati_dasgupta.hotmail.com>
> Sent: 06 July 2020 18:57
> To: AMBER Mailing List<mailto:amber.ambermd.org>
> Subject: Re: [AMBER] FW: restraint 10 kcal/mol
>
> Hello Prof Simmerling,
> Thanks for the detailed reply.
> I was wondering whether FEP could remedy my problem?
> All my small molecule probes ( <15 atoms) are weak binders ~-2 to -3
> kcal/mol and I do not know whether there are any specific set of free
> energy methods that work well in such cases.
> Also Prof Case suggested me to see if there is any intermediate state in
> the protein that allows for the ligand to decouple but at the same time not
> moving away too far from the initial position... I did not understand how
> to achieve that but seems like what you are suggesting is I should restrain
> the ligand and the protein residues as well in the pocket? Will that make
> the results meaningful?
> Regards
> Debarati
>
> Sent from Mail<https://go.microsoft.com/fwlink/?LinkId=550986> for
> Windows 10
>
> From: Carlos Simmerling<mailto:carlos.simmerling.gmail.com>
> Sent: 06 July 2020 11:32
> To: AMBER Mailing List<mailto:amber.ambermd.org>
> Subject: Re: [AMBER] FW: restraint 10 kcal/mol
>
> I have lost track a bit exactly what you're looking for... if you want to
> calculate the absolute binding affinity (quite challenging in my opinion,
> especially when the expected value is very small and probably within the
> uncertainty of the calculation) then you can't use restraints unless you
> also correct your calculated values for the use of the restraint. You might
> want to look at the literature for methods, like that shown in this
> tutorial https://ambermd.org/tutorials/advanced/tutorial29/index.html
> My apologies if you are already doing this, as I said the thread is long
> and I haven't seen all of the messages. Overall I think Dave's point is
> that a positional restraint will not keep your ligand in a pocket (since
> the protein can diffuse away from the ligand). You l;likely want a distance
> restraint or something else involving both the protein and the ligand.
>
>
>
> On Mon, Jul 6, 2020 at 11:16 AM Debarati DasGupta <
> debarati_dasgupta.hotmail.com> wrote:
>
> > Hello Prof Case,
> > I was wondering if I missed your reply on this within so many threads on
> > the list.
> > Regards
> >
> >
> > From: Debarati DasGupta<mailto:debarati_dasgupta.hotmail.com>
> > Sent: 25 June 2020 09:12
> > To: David A Case<mailto:david.case.rutgers.edu>
> > Cc: amber.ambermd.org<mailto:amber.ambermd.org>
> > Subject: Re: [AMBER] restraint 10 kcal/mol
> >
> > Hello Prof Case,
> > Thank you for clearing out the restraint_mask functionality.
> > SO does that mean, in the bigger picture, whatever I did to set up my
> > absolute binding free energy calculations is totally wrong?
> > Using a co-solvent based approach, I have certain x,y,z locations of a
> set
> > small molecules (ethanol, isopropanol, acetonitrile, phenol, pyridine
> etc)
> > and I am interested to compute the absolute free energy of binding (using
> > TI) of these small probes to my kinase.
> > All I know is locations ( in terms of x y z coordinates) where the probe
> > density is maximum, that is, places on the protein where the probe sticks
> > to it.
> > So, given that information, how to modify my input files so that I can
> set
> > up TI calculations to compute free energies of binding.
> > I wanted to mention these are small molecules ( all < 15 atoms) and are
> > weak binders, so the range I am looking at is -1 to -3 kcal/mol roughly..
> > So in your opinion how should I set up the restraint..?
> > Thanks
> >
> > Debarati
> >
> >
> >
> >
> >
> >
> >
> > From: David A Case<mailto:david.case.rutgers.edu>
> > Sent: 24 June 2020 21:36
> > To: Debarati DasGupta<mailto:debarati_dasgupta.hotmail.com>
> > Cc: amber.ambermd.org<mailto:amber.ambermd.org>
> > Subject: Re: restraint 10 kcal/mol
> >
> > On Wed, Jun 24, 2020, Debarati DasGupta wrote:
> >
> > > ntr=1, restraintmask=':EOH', restraint_wt=10.00,
> >
> > Note this will keep the EOH residue from moving, but all other parts of
> > the simulation are free to go where they wish. This doesn't keep the
> > ligand "in the pocket"; it just keeps the xyz coordinates of the EOH
> > atoms near their starting point. Basically, all this will do is to
> > ensure that internal geometry of EOH is kept fixed. I doubt that is
> > really what you wanted to do: since ethanol is rather rigid anyway, this
> > is almost like having no restraint at all.
> >
> > >So, after the run was complete, I was curious to see how far my ligand
> > >has translated from its tether point.. and after doing a COM distance
> > >cpptraj script run, I find that for 3 lambda values 0.11505, 0.20634,
> > >and 0.31608; the ligand has moved around quite a bit as in > 3 Angstroms
> >
> > It's not at all clear what you mean by a "COM distance cpptraj script";
> > but I hope the explanation of the restraint mask above will help.
> >
> > ....dac
> >
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Received on Mon Jul 20 2020 - 07:30:03 PDT
