Hi,
suggestion 1 doesn't work, however, suggestion 2. looks promising.
Here is the setup:
timask1='not_restrained', scmask1='',
timask2='restrained', scmask2=' ,
for lamda = 1
I got :
RESTRAINT = 0.5716
DV/DL = 0.5716
for lambda = 0.5
RESTRAINT = 0.5010
DV/DL = 1.0019
so it it twice the restraint energy
or lambda = 0.0
RESTRAINT = 0.0000
DV/DL = 5.0038
with these three points, this results in dG_restrains_on = +1.9 kcal/mol,
which seems reasonable. However, I am still not sure, whether this is the
right way to do it.
Vlada
> 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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>
>
>
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Received on Thu Mar 26 2015 - 08:30:03 PDT
