On Thu, Apr 9, 2015 at 10:29 PM, windy <chxp_moon.163.com> wrote:
> I saw a paper refering a method to calculate the free energy of a SER
> covalent-orlistat ligand , the substrate orlistat is bound to SER amino
> acid.
>
> But I have used to think that mmpbsa.py is only applied to calculate the
> binding free energy when a ligand and the protein seperately ,no bond exits
> in the ligand and protein.
>
Correct, MM/PBSA (or any end-state free energy method, for that matter)
only works for noncovalent binding events.
> I donnot know how to calculate the system when a ligand bond to protein.
> The system exits widely when you'd like to study the enzyme catalyse
> mechanism.
>
There are a number of ways that this can be done. If you can devise a
thermodynamic cycle in which one of the legs of that cycle corresponds to a
simple system that you can compare directly to experiment, then you can use
thermodynamic integration to "transform" the ligand into whatever attacking
group replaces the covalent bond to the ligand.
This is the most general route and gives you the absolute binding free
energy.
Another option is to define a reaction coordinate that correlates with the
binding mechanism that you anticipate. Then you can use a QM/MM approach
to treat the ligand quantum mechanically and use a method like umbrella
sampling or steered molecular dynamics in order to "pull" the reaction
along the coordinate you defined (perhaps just a simple distance from the
bound state to a certain separation from some key active site residues).
At the end of the day, you will need a method that can deal with breaking
bonds, and that reduces to either an alchemical method like FEP or TI (but
you need a reference reaction that you can tune to experimental values) or
a QM/MM approach along a reaction coordinate.
You may find some of the tutorials at
http://ambermd.org/tutorials
enlightening (particularly the one using steered MD to model a proton
transfer).
HTH,
Jason
--
Jason M. Swails
BioMaPS,
Rutgers University
Postdoctoral Researcher
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Received on Fri Apr 10 2015 - 03:30:02 PDT
