ram bio wrote:
Dear Mark,
Thanks and you are right, that when a docked complex (protein +
ligand) is simulated, the favorable ligand binding poses can be
predicted using MD (longer runs). What I am trying to do here
presently is not to simulate a docked complex, but to generate a
modelled protein lowest energy configuration (P.E. surface
exploration) using MD and further use this configuration for the
flexible docking, and you are right as I think MD follows the law of
conservation of energy as the P.E decreases the K.E increases or vice
Sure, under NVE, and even approximately so under other ensembles.
versa for a configuration at an instance, as we are exploring the P.E
surface by changing the coordinates very effectively using M.D, i want
use the configuration (coordinates) with the lowest P.E produced from
MD and further minimize it (as i dont know whether the configuration
obtained after gromacs MD can go further into a local/global minima by
minimization) so that can be the input for flexible docking.
MD *as a sampling tool* is all very well, but the structures you want to
get from the sample are not necessarily the low PE ones. You want the
ones representative of the *free energy* minima, which need not
correlate at all with low PE :-) Constructing such a free energy surface
is a non-trivial undertaking, which is why people historically clustered
trajectories, etc.
This comes back to how the docking methodology was derived. If their
ligand binding targets were energy minimized to a certain degree, then
you should probably reproduce that method on whatever you take for your
set of target conformations. Hopefully their parameterization can deal
with the intrinsic paradoxes of the situation. However if the target has
some other structure, or range of structures, in the real system, then
you have a (garbage in -> garbage out) docking study. Hence wanting a
range of targets chosen by a useful criterion - or at least a study
demonstrating that a small range is representative.
Either way, long MD (maybe REMD) and something like clustering of the
output trajectories is a much sounder approach. But perhaps the docking
forcefield is so random that it doesn't matter much :-) Literature is
your friend (and I make no claim of being current with docking literature!)
Mark
On Thu, Oct 22, 2009 at 4:59 PM, Mark Abraham <mark.abra...@anu.edu.au> wrote:
ram bio wrote:
Dear Mark,
You mean that I should consider a configuration with the lowest total
energy for docking studies..Please clarify and suggest me.
If you read your docking program's documentation, they are using their
"energy" as a some kind of approximation to a free energy of ligand binding
(or some such). There could be all kinds of ad-hoc contributions that they
may have been able to demonstrate worked usefully enough on their test set
to be worth including.
There's no reason to assume an MD potential "energy" (which itself is a
combination of more-or-less ad-hoc parameters) would correlate with the
above, since the MD potential wasn't parameterized to do that. It'd be
especially flawed to suppose that the fact that energy in MD is distributed
over PE and KE is immaterial. Low PE just means high KE.
To identify favourable ligand-binding orientations with MD requires an
immense amount of sampling. In effect, you need to do enough MD to allow the
ligand to come in and out of the site many times in many different ways and
to compare the relative frequency so that you can also estimate the entropy
component of the free energy change associated with various binding modes
relative to each other. Even for implicit solvent calculation models, the
history of computing probably doesn't provide enough cycles to do this with
decent accuracy. Hence, docking.
MD can be useful in more limited "docking" studies - a highly unfavourable
binding conformation will fly apart rapidly - but you'd hope the docking
force field could tell you about those cases!
It sounds like you should really be doing some more background reading about
docking and MD, to better understand the methods you're using.
Mark
On Thu, Oct 22, 2009 at 3:56 AM, Mark Abraham <mark.abra...@anu.edu.au>
wrote:
ram bio wrote:
Dear Justin,
Thanks for the suggestion and advice.
As i have used a modelled protein and want to obtain the lowest energy
configuration of the protein by doing dynamics,
That's all very well, but what will that give you other than a set where
the
partition of total energy into potential and kinetic was skewed one way?
Mark
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