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From: <hannes.loeffler.stfc.ac.uk>

Date: Thu, 26 Mar 2015 07:32:07 +0000

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

Received on Thu Mar 26 2015 - 01:00:02 PDT

Date: Thu, 26 Mar 2015 07:32:07 +0000

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

Received on Thu Mar 26 2015 - 01:00:02 PDT

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