you could take a look at some recent work from my group on a similar
problem. Standard MD was not enough to obtain reliable data.
ACS Chem Biol. <
http://www.ncbi.nlm.nih.gov/pubmed/24527857#> 2014 Apr
18;9(4):986-93. doi: 10.1021/cb400896g. Epub 2014 Mar 10.
A structural and energetic model for the slow-onset inhibition of the
Mycobacterium tuberculosis enoyl-ACP reductase InhA.
On Thu, Nov 27, 2014 at 6:44 AM, anu chandra <anu80125.gmail.com> wrote:
> Thanks for the immediate reply.
>
> On Wed, Nov 26, 2014 at 10:42 PM, Carlos Simmerling <
> carlos.simmerling.gmail.com> wrote:
>
> > You haven't given us much info. First, you need to ensure that these
> basins
> > are all reliable and reproducible. Free energies from straight md are
> > notoriously unreliable and it's easy to over interpret the results. Make
> > sure you can physically justify them as well and they are not just noise.
> >
> > To get back to your question, you ask about the "initial stage of
> > simulation". What exactly takes place in this simulation? What are you
> > doing? What do you mean "change while ligand binding"? Are you forcing
> > binding to occur?
> >
> One way to get the insight you're looking for is to map the time dependence
> > of the projection of each snapshot onto the pca modes. That way you can
> map
> > basins to structures. Explaining what's going on would then take some
> > structural biology insight, knowledge of your specific system, and most
> > likely design of followup data analysis to confirm that what you see in
> the
> > snapshots is actually a well sampled property in the MD run and not just
> an
> > artifact of looking at a subset of the snapshots. Then you would use this
> > information to compare to experimental data, keeping in mind all of the
> > potential weaknesses of your simulation. Ideally you will make specific
> > predictions that are then confirmed through experiments.
> >
>
> In the apo system, ligand binding pocket of the protein shift between open
> and closed state, where in ligand bound system the pocket get locked in its
> closed state. It seems like the closed and open state have very narrow
> energy barrier as it can be sampled during all-atom classical MD. In apo
> simulation, the free energy landscape from principal modes shows six
> low-energy basins and mapped structures from different basins could able to
> explain the closed and open states. However, I would like to see what could
> be the possible direction of exploring these different minima in the
> landscape during simulation?
>
> Many thanks
>
> Anu
>
> On Nov 26, 2014 6:07 AM, "anu chandra" <anu80125.gmail.com> wrote:
> >
> > > Dear Amber users,
> > >
> > > I am working with MD simulation of protein -ligand interaction. In
> order
> > to
> > > get information about subtle change in protein while ligand binding, I
> > have
> > > carried out principal component analysis (PCA). I have also drawn the
> > free
> > > energy landscape using PC1 and PC2, which came up with five low-energy
> > > basins. is there a way to identify which basin will be encountered at
> the
> > > initial stage of simulation?
> > >
> > > Many thanks,
> > >
> > > Anu
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Received on Thu Dec 11 2014 - 06:30:02 PST
