I have two questions:
1) How certain are you that the configuration when you start production is
actually the minimum energy configuration? You might need to do some
restrained dynamics or biased dynamics in order to get the ligand into a
better orientation where it interacts more strongly with the binding site.
2) How are the parameters for the ligand parameterized? Different partial
charges can make a large difference in the binding affinity.
On Sun, Feb 19, 2012 at 6:30 PM, tian zhu <tzhu6.uic.edu> wrote:
> Dear AMBER users,
>
> I am currently using MD and MM/PBSA to investigate the binding modes and
> energies of small ligands ("fragments" with MW <250 Da) binding in the
> active site of my target enzyme. *The binding pocket is solvent exposed and
> relatively small. And the ligands are relatively small with weak binding
> affinities. *After ~500 ps equilibrium, I ran 8 ns MD. Between 1-2 ns of
> production phase, I observed the ligand slowly ran out from the binding
> pocket. *My questions are*: should I apply a small constraining force in
> order to keep these small ligands in the binding pocket, if so, then how
> to subtract this energy when MM/PBSA is applied to calculate the binding
> energy of the complex? Or should I refine my equilibrium and MD protocol to
> be gentler so that the ligand might stay in active site for longer time? Or
> should I just leave it as it is (not all of them ran out of pockets, just
> around half of these small ligands did)?
>
> MD preparation details are listed in below and the input files are
> attached:
> 1. small ligands were docked into the active site and two conformations for
> each were kept for MD runs.
> 2. two steps minimization (waters; whole system).
> 3. heat (Langevin temperature control; restraint_wt=2.0; 50 ps), density
> (restraint_wt=2.0; 50 ps) and equilibration (restraint_wt=0.5; 500 ps).
> 4. production (8 ns)
>
> Thanks,
> Tian
> Graduate student
> College of Pharmacy
> University of Illinois at Chicago
>
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>
>
--
Aron Broom M.Sc
PhD Student
Department of Chemistry
University of Waterloo
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Received on Sun Feb 19 2012 - 20:30:01 PST
