On 7/26/11 11:32 AM, Sergey Samsonov wrote:
> Dear all,
>
> I've been starting testing steered MD for some systems in order to apply
> it for protein-protein interactions analysis and I've been searching the
> literature on this topic. I have some related questions, which maybe you
> could help me to answer.
some VERY biased answers below !
>
> 1. Force of pulling proteins or receptor/ligand apart. In AMBER 10
> manual example the constant of 5000 kcal/(mol A^2) is used. In the
> literature I've seen absolutely different ranges of these values (down
> to 1kcal/(mol A^2)). The explanations are a bit controversial: in some
> papers the authors claim that the constant should be comparable to kT/2,
> in other that this constant should be essentially higher in order to
> have less effects from thermal motions. What do you think is appropriate
> and what is the best way to optimize this constant for each individual
> system? For pulling ion apart from the protein I noticed quite a
> significant influence of this constant on the calculated free energy.
First, kT/2 has units of kcal/mol while the force constant has units of
1kcal/(mol A^2) (for a distance), so the text 'The explanations are a
bit controversial: in some papers the authors claim that the constant
should be comparable to kT/2,in other that this constant should be
essentially higher in order to have less effects from thermal motions.'
makes no sense. Can you make it clearer what you mean ?
The value of the force constant AND the speed of pulling depend
crucially in what you want to do. Are you using this data to get some
general idea of the protein-protein association pathway or you really
want the free energy? If you want the free energy, then you need to
repeat the pulling MANY times, from an initially 'equilibrated' sampled,
where all the snapshots have the same distance. Then, look at Schulten
papers where he describes the so-called stiff spring approximation. The
force constant CANNOT be very small, otherwise what the pulling spring
and your molecules are doing is very different. Basically, you pull with
a soft spring, and the molecule just does not care and does not follow
the distance.
>
> 2. Speed of pulling. Again, I found various values in the literature
> with the range from 1 to 100 A/ns. Am I right if I consider an ability
> of the simulation to keep the structures of pulled apart proteins
> undistorted as one of the most important criteria for the selection of
> this parameter?
The speed of pulling is extremely system dependent. For free energies,
there are too many tricks to do to explain in this space. Take a look at
the paper below for some ideas.
Xiong, Hui; Crespo, Alejandro; Marti, Marcelo; Estrin, Dario; Roitberg,
Adrian E.. Theoretical Chemistry Accounts. 116(1-3):338-346 (2006)
>
> 3. Is there an explicit way in AMBER (I use AMBER 10) to apply the
> pulling forces to the centers of masses of protein/protein pair or to
> all backbone atoms instead of choosing only two atoms? Otherwise could
> an alternative solution be just putting restraints on backbone or
> C-alpha atoms of the proteins and applying the pulling force on two
> atoms (though this sounds to me being physically more ambiguous)?
Yes, look at group restraints. You can set a distance between center of
masses of group for instance. Look at the manual also for natural
language restraints.
>
> 4. Is there the way in Leap to create an assymetric water box for PBC
> with an elongated side, along which the pulling is occuring? This would
> save the computational expenses a lot in case of SMD.
I am pretty sure this is not needed ! Since you are using PBC, the box
is never really assymetric anyways. If you have your molecule to one
side of the box, then the molecular in the next box is also displaced,
so you gain nothing.
Adrian
>
> Thank you very much in advance!
>
> Best regards,
>
> Sergey
>
--
Dr. Adrian E. Roitberg
Full Professor
Quantum Theory Project, Department of Chemistry
University of Florida
on Sabbatical in Barcelona until August 2011.
Email roitberg.ufl.edu
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Received on Tue Jul 26 2011 - 03:30:02 PDT
