[gmx-users] Free energy change with harmonic restraints

Sun Jul 12 08:54:16 CEST 2015

Dear Natalie,

The weekend was good. Thanks. I hope that you have a great weekend too.

If you manage to simulate the system with restraints (A) and without  
restraints (B) you can calculate the free energy difference between  
A/B to a system in which the ligand is not interacting with the  
environment (protein and solvent) at all. The free energy associated  
with the restraints when the ligand is not interacting via VDW and  
electrostatic interactions with the environment can be calculated with  
the analytic expressions.

In summary you can calculate Delta F_{A->A'} and F_{B->B'} where A'  
and B' are when the ligand is not interacting via VDW and  
electrostatic interactions with the environment without and with  
restraints respectively. This can be calculated by TI, Bar etc. Then  
there is to calculate F_{B'->B''} where this free energy difference is  
given by the analytic equations. F_B''=F_A' since it's a system in  
which the ligand is not interacting with the environment (protein and  
solvent) at all. Thus you can calculate F_{A->A'} and F_{B->B''} and  
obtain F_{A->B}.

I hope it helps.

Best regards,
Asaf

Quoting Natalie Nguyen <nguyenn at wittenberg.edu>:

> Dear Asaf,
>
> I hope you have had a great weekend!
> I have tried applying TI with restraint-lambdas to measure the free  
> energy difference of applying restraints without success (no dhdl  
> files were being outputted). The tutorial in the link provided by  
> Hannes Loeffler I have looked over before, but my intentions are not  
> measuring the free energy change of binding.
> I would like to know in more detail on how to approach this.
>
> Much appreciated,
> Natalie
>
> ________________________________________
> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se  
> <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of  
> asaffarhi at post.tau.ac.il <asaffarhi at post.tau.ac.il>
> Sent: Thursday, July 09, 2015 5:58 PM
> To: gromacs.org_gmx-users at maillist.sys.kth.se
> Subject: Re: [gmx-users] Free energy change with harmonic restraints
>
> Dear Natalie,
>
> What I can say is that e.g Thermodynamic Integration should give the
> free energy difference of this transformation. If you are interested
> in the free energy of binding the link provided to you by Hannes
> Loeffler may be useful. Also, for such a k value in case you will need
> analytic equations it will be better to use the exact equations (the
> equations in this link are approximate). I'll supply an exact equation
> if you'll need for the free energy of a dihedral harmonic term.
>
> I hope to have more time next week and give more details (the weekend
> starts here).
>
> Best regards,
> Asaf
>
> I hope to have more time next week and to try
>
> Quoting Natalie Nguyen <nguyenn at wittenberg.edu>:
>
>> Dear Asaf,
>>
>> Thank you again for putting in the time to respond to me so quickly.
>> What I have been trying to do was start from a system that is not
>> restrained and grow the restraints onto the ligand, measuring the
>> change in free energy of this. The harmonic restraints used are that
>> of the umbrella pull code with a force constant of k= 1000
>> kJ/mol*nm^2. It is mentioned In the Gromacs manual for mdp options
>> that the pull code can be controlled with "restraint-lambdas", but
>> there is not much detail other than this. I imagine that lambda =0
>> would represent a nonexistent potential with k= 0 and at lambda = 1
>> a full strength potential would be imposed.
>> Please feel free to ask me to add more detail!
>>
>> Warm regards,
>> Natalie
>>
>> ________________________________________
>> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se
>> <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of
>> asaffarhi at post.tau.ac.il <asaffarhi at post.tau.ac.il>
>> Sent: Thursday, July 09, 2015 10:38 AM
>> To: gromacs.org_gmx-users at maillist.sys.kth.se
>> Subject: Re: [gmx-users] Free energy change with harmonic restraints
>>
>> Dear Natalie,
>>
>> You are welcome.
>> Could you please explain in more detail so maybe I can help?
>> Do you want to change the strength of the restraints and measure the
>> free energy difference associated with this change?
>>
>> Thanks. p.s there is also http://arxiv.org/pdf/1307.1620v7.pdf with
>> the same equations.
>>
>> Best regards,
>> Asaf
>>
>> Quoting Natalie Nguyen <nguyenn at wittenberg.edu>:
>>
>>> Dear Asaf,
>>>
>>> Thank you for the quick reply!
>>>
>>> I was wondering if it was possible to use thermodynamic integration
>>> to represent growing harmonic restraints aside from using an
>>> analytical method.
>>>
>>> I will cite this article most definitely!
>>>
>>> Natalie Nguyen
>>>
>>> ________________________________________
>>> From: gromacs.org_gmx-users-bounces at maillist.sys.kth.se
>>> <gromacs.org_gmx-users-bounces at maillist.sys.kth.se> on behalf of
>>> asaffarhi at post.tau.ac.il <asaffarhi at post.tau.ac.il>
>>> Sent: Thursday, July 09, 2015 7:45 AM
>>> To: gromacs.org_gmx-users at maillist.sys.kth.se
>>> Subject: Re: [gmx-users] Free energy change with harmonic restraints
>>>
>>> Dear Natalie,
>>>
>>> You have in
>>>
>>> http://xxx.tau.ac.il/pdf/1502.07196v3.pdf
>>>
>>> exact free energy of harmonic covalent bond and bond angle terms (or
>>> restrains). See Eqs. (2) and (3).
>>>
>>> There are also previous studies in the references there.
>>>
>>> For the dihedral term I assume it can also be calculated exactly (I
>>> might upload it).
>>>
>>> There is also to think if there are other contributions.
>>>
>>> If you are using it please cite.
>>>
>>> Best regards,
>>> Asaf
>>>
>>>
>>> Quoting Natalie Nguyen <nguyenn at wittenberg.edu>:
>>>
>>>> Dear all,
>>>>
>>>>
>>>> I am trying to measure the free energy change associated with
>>>> adding/removing harmonic restraints imposed on a ligand that is
>>>> attached to a protein. Is there any way to set this up?
>>>>
>>>>
>>>> Thank you ahead of time!
>>>>
>>>>
>>>> Natalie Nguyen
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>>
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