Hi again,
I have not done this by myself so I can only make suggestions how I _think_ this may work. So you will have to experiment unless you get an answer form someone more knowledgeable.
Set nmropt=1 and define the necessary &wt namelist to define your restraints. I assume you can define multiple restraints simultaneously. If not you would have to do it one-by-one... At the end you are interested in scaling only those restraints with lambda and nothing else.
Suggestion 1:
Create a prmtop file with only one ligand. I assume that's exactly the prmtop you already have for the annihilation step (mutate ligand to nothing). Set icfe=1, ifsc=0 and the timasks and scmasks to empty strings. The hope here is that pmemd would only lambda scale the NMR restraints. I do not know if using empty strings would switch off the TI code or this doesn't work for some other reason. If so
Suggestion 2:
Create a prmtop file with two identical copies of the ligand (that's how you would setup relative free energy simulations). Set icfe=1, ifsc=0 and timask1 to the first ligand and timask2 to the second ligand. The scmasks stay empty (which also implies ifsc=0). In this way ligand 1 would be transformed into ligand 2 but since all force field parameters are identical the resulting free energy should be zero. Not very sufficient obviously so I hope suggestion 1 just works out for you.
Please report back if any of this works.
Thanks.,
Hannes.
________________________________________
From: vladimir.palivec.marge.uochb.cas.cz [vladimir.palivec.marge.uochb.cas.cz]
Sent: 26 March 2015 08:34
To: AMBER Mailing List
Subject: Re: [AMBER] Free energy calculation: Thermodynamic integration with use of restraints
Hello,
thank you for an advice. This might be relly the way, however, I do not
know how to perform this step. I dont know how to couple a system between
free and restrained state (how exatly to do it, as in the manual there is
not a word about this).
Please, can you give me any suggestions?
> I just realise that in both sander and pmemd, NMR restraints (nmropt=1)
> are scaled too as per the link in your original email. This may be the
> better option to pursue.
>
> ________________________________________
> From: Loeffler, Hannes (STFC,DL,SC)
> Sent: 25 March 2015 19:12
> To: AMBER Mailing List
> Subject: RE: [AMBER] Free energy calculation: Thermodynamic integration
> with use of restraints
>
> So, what you want to do is an "absolute" free energy calculation with the
> TI code. You also want to only couple a set of restraints to lambda. If
> I understand the Boresch' method correctly you would need to define six
> such restraints: one bond, two angles, three dihedrals. Right?
>
> Sorry, I'm not too well at the moment so I may get this wrong but wouldn't
> it be possible to define those restraints in terms of existing atoms and
> introduce additional bonds, angles and dihedrals between them. In the
> input file you would then define the TI region by including those atoms
> only while the softcore mask is empty. Maybe that's a plan but I would
> have to rethink it. The only other idea I can come up with is to create
> multiple topology files with those additional terms pre-scaled by the
> current lambda but then you would need to do a EXP/BAR estimation for the
> associated free energy as I can't see at the moment how this could be fit
> into the TI formalism.
>
> Cheers,
> Hannes.
>
> ________________________________________
> From: vladimir.palivec.marge.uochb.cas.cz
> [vladimir.palivec.marge.uochb.cas.cz]
> Sent: 25 March 2015 17:55
> To: amber.ambermd.org
> Subject: [AMBER] Free energy calculation: Thermodynamic integration with
> use of restraints
>
> Hello,
>
> this question is similar to this one:
>
> http://archive.ambermd.org/201205/0093.html
>
> however, I think I quite did not get it.
>
> I would like to do a thermodynamic integration simulations to calculate dG
> of binding of a ligand to a protein. After search through a literature I
> decided to do it in multiple steps:
>
> 1. constrain a ligand in a certain position using 6 restraints
> - here i need to calculate dG of proposing restraints
>
> 2. turn off el. i.
>
> 3. using soft core, turn off vww interactions
>
> 4. analytically remove restraints
>
>
> I am not sure how to perform the step 1. I thought it is possible to use
> pmemd with single topology and gradually propose restraints and thus get
> the dG (with use of nmropt=1 and DIANG file). However, I have no found any
> way to do it - either in manual or forum. Please, can somebody give me a
> hint how this calculation should be performed? How to set up the
> calculation and how to obtain energy of proposing restraints?
>
> Is it even possible to do it with one topology file?
>
> Thank you very much for any help!
>
> Vlada
>
>
>
>
>
>
>
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Received on Thu Mar 26 2015 - 02:30:03 PDT
