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From: <vladimir.palivec.marge.uochb.cas.cz>

Date: Thu, 26 Mar 2015 16:22:03 +0100

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
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> _______________________________________________
*

*>> AMBER mailing list
*

*>> AMBER.ambermd.org
*

*>> http://lists.ambermd.org/mailman/listinfo/amber
*

*>>
*

*>> _______________________________________________
*

*>> AMBER mailing list
*

*>> AMBER.ambermd.org
*

*>> http://lists.ambermd.org/mailman/listinfo/amber
*

*>>
*

*>
*

*>
*

*>
*

*> _______________________________________________
*

*> AMBER mailing list
*

*> AMBER.ambermd.org
*

*> http://lists.ambermd.org/mailman/listinfo/amber
*

*>
*

*> _______________________________________________
*

*> AMBER mailing list
*

*> AMBER.ambermd.org
*

*> http://lists.ambermd.org/mailman/listinfo/amber
*

*>
*

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Received on Thu Mar 26 2015 - 08:30:03 PDT

Date: Thu, 26 Mar 2015 16:22:03 +0100

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

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AMBER mailing list

AMBER.ambermd.org

http://lists.ambermd.org/mailman/listinfo/amber

Received on Thu Mar 26 2015 - 08:30:03 PDT

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