[gmx-users] Constrains and TI

[Maik Goette]

That sounds more reasonable...:)

In fact I like the idea of using distance restraints, but I still doubt, 
that will work...

I would really suggest to use the TI method. If you apply it properly it 
should give reasonable results. With proper application, speaking about 
using soft-core for VdW (with good parameters), hardcore for qq, back 
and forth morphing for an idea of the hysteresis or using discrete TI 
instead of slow-growth, etc. you should get reasonable results. But 
depending on your perturbation size this could also be a hard task, to 
obtain correct numbers and not just building the famous costly random 
number generator...

Regards

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:
> 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:
>> 1. Reading the manual
>> 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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> 
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