# [gmx-users] Constrains and TI

bmmothan at ucalgary.ca bmmothan at ucalgary.ca
Wed Aug 8 19:38:41 CEST 2007

```Thank you for the reply,

Sorry for the confusion of my two emails. I guess I was using the word
"pulling" in the wrong context. Now after my extensive reading, what I
meant  is that i want to calculate the absoulte binding free energy of a
ligand/receptor complex.

I have read the manual over and looked at the tutorials, and came to the
idea that i can constrain distances b/w the ligand and the receptor and
input a distance for state B to vary the distance using lamda. (Manual 3.3
chapter 6 special topics, section 6.3 Calcuating the PMF using the
free-energy code)

I am using contraints type 2, which can be perturbed in free energy
calculations. here is what I used in my calculation:
[ constraints ]
; ai   aj  funct  length_A  length_B
44   258   2     0.259    2.406
123  179   2     0.329    2.334

I am currently running a 5ns using the slow-growth method to give me an
idea of what happens to the system.

I am also looking into using orientational-restrains and using a
thermodynamic cycle instead of PMF of the unbinding of the ligand to
receptor.

please correct me if I am wrong.

and thanks for ur help.

Belquis

> Hi
>
> First, for the other topic you posted (which is probably somehow related
> to this one):
>
> Now, please be more specific with what you want to do....You wrote:
> "What I want to do is calculate the free energy difference of pulling
> the ligand away from the receptor"
>
> This is a pulling approach, where you would like to do AFM sims and
> afterwards use Jarzynski. If that is what you want, search the
> literature for Jarzynski and try to understand his theorem (you will
> see, one pulling sim is not enough for free energy calc).
>
> Then you wrote:
> "I want to do it using theromdynamic intergration using the Lamda 0/1
> stuff"
>
> This is a totally different approach....
>
> With both, you can ESTIMATE binding free energies. Still, both are very
> different in the way to setup a simulation in GROMACS. You WILL find
> out, how to do it by:
> 2. Searching the mailing list
> 3. Using the GROMACS Wiki
> 4. Using some of the tutorials, which were posted, by e.g. David Mobley
>
> Now, coming to your idea about using distance restraints to "pull" the
> ligand away (its more of a push).
> I think (correct me if I'm wrong), that you can't use A and B state
> distance restraints in GROMACS (or better say, they will stay the same
> for both states).
>
> I'd suggest to use either TI OR AFM pulling. For sure, you could do both
> and see, if you get similar free energy differences with both methods...
> I don't think, you can calculate the free energy difference by using
> different distance restraints, anyway.
>
> Regards
>
> P.S.
> As I just saw it. Inform yourself about the difference between
> CONSTRAINTS and RESTRAINTS (there is an important one...)
>
> Maik Goette, Dipl. Biol.
> Max Planck Institute for Biophysical Chemistry
> Theoretical & computational biophysics department
> Am Fassberg 11
> 37077 Goettingen
> Germany
> Tel.  : ++49 551 201 2310
> Fax   : ++49 551 201 2302
> Email : mgoette[at]mpi-bpc.mpg.de
>          mgoette2[at]gwdg.de
> WWW   : http://www.mpibpc.gwdg.de/groups/grubmueller/
>
>
> bmmothan at ucalgary.ca wrote:
>> hello all,
>>
>>
>> is it possible to constrain a distance (or several) between a
>> ligand-receptor complex inorder to simulate free energy change of
>> separating the ligand from the receptor?
>>
>> I intend to use TI and lamda to do free energy calculations.
>>
>>
>> any help is appreicated.
>>
>> Belquis
>>
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