[gmx-users] Protein Solvent Dynamics - Coordinates for docking

[ram bio]

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
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.


Thanks,

Ram

On Thu, Oct 22, 2009 at 4:59 PM, Mark Abraham <Mark.Abraham at 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.Abraham at 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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